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From: [e-mail] (Dave Kristofferson)
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Subject: NIH Guide, vol. 21, no. 42, pt. 2, 20 November 1992
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Date: 21 Nov 92 04:19:38 GMT
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$$XID NIHGUIDE 19921120 V21N42 P2O2 ************************************
or delivered to:

Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW PROCEDURES

Applications will be reviewed by the NIH Division of Research Grants
(DRG).  The review criteria are the traditional considerations
underlying scientific merit.  Applications will be reviewed by standard
NIH review procedures in accordance with the usual NIH peer review
procedures, based on scientific merit.  Following study section review,
the applications will be evaluated by the appropriate national advisory
council.

The review criteria for each mechanism may be obtained from the program
contact listed below.

AWARD CRITERIA

Applications will compete for available funds on the basis of
scientific merit with other applications.  The following will be
considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program balance among research areas of the announcement

INQUIRIES

The opportunity to clarify any issues and questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Pamela Starke-Reed, Ph.D., Geriatrics Program, Suite 3E327
Telephone:  [phone]

Huber Warner, Ph.D., Biology of Aging Program, Suite 2C231
Telephone:  [phone]

Marcia Ory, Ph.D., M.P.H., Behavioral and Social Research Program,
Suite 2C234
Telephone:  [phone]

Andrew Monjan, Ph.D., Neuroscience and Neuropsychology of Aging
Program, Suite 3C307
Telephone:  [phone]

All are at the NIA with the following address:

National Institute on Aging
Gateway Building
Bethesda, MD  20892

or

Rick Martinez, M.D.  or  Enid Light, Ph.D.
Mental Disorders of the Aging Research Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7-103
Rockville, MD  20857
Telephone:  [phone]

Direct inquiries regarding fiscal matters to:

Barbara Cunningham
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892
Telephone:  [phone]

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.866.  Awards are made under authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410), as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This
program is not subject to the intergovernmental review requirements of
Executive Order 12372 or Health Systems Agency review.

$$P2 END ************************************************************

$$P3 BEGIN PA-93-23 *************************************************

HEMOGLOBIN-BASED OXYGEN CARRIERS:  MECHANISMS OF TOXICITY

NIH GUIDE, Volume 21, Number 42, November 20, 1992

PA:  PA-93-23

P.T. 34; K.W. 0785070, 1003002, 1002004, 1002008, 0710100, 0765035

National Heart, Lung, and Blood Institute

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) announces a
Program Announcement (PA) on the above subject.  The purpose of this
initiative is to encourage research aimed at providing an understanding
of the mechanisms of toxicity of hemoglobin-based oxygen carriers.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This PA,
Hemoglobin-based Oxygen Carriers:  Mechanisms of Toxicity, is related
to the priority area of food and drug safety.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone [phone]).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by foreign and domestic, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal Government.
Applications from minority individuals and women are encouraged.
Awards in connection with this announcement will be made to foreign
institutions only for research of very unusual merit, need and promise,
and in accordance with PHS policy governing such awards.  Foreign
institutions are not eligible for First Independent Research Support
and Transition (FIRST) (R29) awards.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research
project grant (R01) and FIRST (R29) award.  Applicants, who will plan
and execute their own research programs, are requested to furnish their
own estimates of the time required to achieve the objectives of the
proposed research project.  Up to five years of support may be
requested.  Because the nature and scope of the research proposed in
response to this PA may vary, it is anticipated that the size of an
award will also vary.  Those applicants requesting support under the
FIRST (R29) award should be certain that the direct costs requested are
within the guidelines for that award.  Administrative adjustments in
project period and/or amount of support may be required at the time of
the award.  All current policies and requirements that govern the
research grant programs of the NIH will apply to grants awarded in
connection with this PA.

RESEARCH OBJECTIVES

Background

An alternative to red blood cells for transfusion has been sought
unsuccessfully for over one hundred years.  In recent years, the NHLBI
and other government agencies have supported research on the
development of stable oxygen carriers that do not need to be
cross-matched and that can be stored for extended periods of time.
During the past decade, awareness of the dangers inherent in
transfusion of homologous red blood cells has heightened.  These
include transmission of infectious agents such as HIV, hepatitis
viruses and other microorganisms.  Consequently, physicians are
increasingly reluctant to transfuse their patients and patients are
increasingly reluctant to receive blood.  Although testing of units of
blood is becoming more comprehensive and efficient, there is no
question that products that are free of infectious agents that could be
used in place of red cells would have wide clinical application.  In
spite of this promise, studies of hemoglobin-based oxygen carriers have
been disappointing as unpredictable toxicities have thwarted
development of clinically useful products.

Infusion of hemoglobin-based oxygen carriers into the circulation can
result in a variety of outcomes.  Carrier molecules may leave the
circulation by a number of routes including endothelial transcytosis,
phagocytic uptake, and diffusion.  The effects of these materials may
be as diverse as the range of properties of the various tissues they
bathe.  Their interaction with endothelium-derived relaxing factors,
stimulation of other vasoactive materials, and stimulation of mediators
of inflammation may add to the complex biological reactions noted in
research to date.  Furthermore, much of the previous work in this field
is clouded by species differences, so that, at present, there are no
animal or in vitro models that will reliably predict human reactions.

In addition to Federal support, research and development of artificial
oxygen carriers have been carried out by industry.  Indeed, industry
has contributed valuable knowledge in the area of product and quality
control.  Sophisticated high technology systems have been developed to
produce products in large quantities.  However, in recent clinical
trials with hemoglobin-based oxygen carriers, unexpected toxicities
were observed suggesting the need for more basic research to address
fundamental questions concerning interaction with the immune system and
endothelium in particular.

Research Objectives and Experimental Approaches

The purpose of this PA is to encourage research aimed at providing an
understanding of the mechanisms of toxicity of hemoglobin-based oxygen
carriers.  This program encourages research addressing such fundamental
questions as:  (1) what are the mechanisms of vasoactivity of
hemoglobin solutions, (2) how do protein modifications affect
vasoactivity, (3) what are the mechanisms of stimulation of
inflammation mediators by hemoglobin-based oxygen carriers, (4) how can
this stimulation be prevented, (5) what animal or in vitro models are
best used to study toxic effects of oxygen carriers, (6) what are the
long-term (metabolic and pharmacologic) effects of oxygen carriers, and
(7) what models are best to demonstrate efficacy in terms of oxygen
transport to tissue.  Particular encouragement is offered to
investigators possessing modern tools, who are well-trained, and who
are currently pursuing other research interests to devote time and
resources to this area.  It is hoped that interdisciplinary and
collaborative approaches may be developed which will complement the
efforts of workers in the field.  The ultimate goal is to satisfy a
fundamental need in clinical medicine, i.e., development of a safe,
economical and efficacious alternative to homologous human red blood
cells for transfusion.

Examples of promising topics are:

o  Studies of the interaction of hemoglobin with endothelium and
macrophages.
o  Development of animal models that simulate clinical use, such as
trauma, shock, infection, and surgical blood loss.
o  Studies relating the biochemical modification of hemoglobin with its
biological effects.
o  Studies of encapsulation of hemoglobin into artificial vesicles -
biochemical, physical, physiological, and biological effects.
o  Studies of the tissue distribution and metabolic fate of modified
hemoglobins, and artificial vesicles.

These are intended as examples only.  Investigators are encouraged to
consider other innovative approaches.

Applications may address one or several issues, but should retain a
common theme and focus on addressing those issues.  Because issues
involving hematology, biochemistry, physiology, cell biology,
pharmacology or molecular biology may need to be addressed in a
coordinated manner, collaboration among investigators having expertise
in these and other appropriate disciplines is encouraged.  When
individuals are at different institutions, individual R01 applications
may include consortium arrangements.

While the main focus of this PA is on basic or fundamental research
studies to elucidate the mechanisms of toxicity of hemoglobin-based
oxygen carriers, clinical studies, but not clinical trials, are also
appropriate.  Collaborative arrangements with ongoing clinical studies
or trials that provide patient material at little or no cost to the
applicant are also encouraged.  Such arrangements should be clearly
delineated in the application.  The description should include
sufficient information to permit scientific evaluation of the studies
proposed.  Among issues to include are the number and type of
specimens/patients, patient population characteristics (including
gender and minority composition; see STUDY POPULATIONS below), overall
goals of the collaborative project, remaining term of the project, and
IRB approval of the project.  If substantial interactions and costs
with ongoing projects are proposed, a consortium agreement can be
developed and submitted to support this additional research aspect.

If statistical analysis is anticipated, the methodologies and personnel
involved should be described in the application and evident in the
study design.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and women
in study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis should be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to apply
to males and females of all ages.  If women or minorities are excluded
or inadequately represented in clinical research, particularly in
proposed population-based studies, a clear compelling rationale should
be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues should be addressed in developing a research
design and sample size appropriate for the scientific objectives of the
study.  This information must be included in the form PHS 398 (rev.
9/91) in Sections 1-4 of the Research Plan AND summarized in Section 5,
Human Subjects.  Applicants are urged to assess carefully the
feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans including American Indians or Alaskan Natives,
Asian/Pacific Islanders, Blacks, and Hispanics).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, (and
preventive strategies), diagnosis, or treatment of diseases, disorders
or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the  results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and will be reflected in
assigning the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398
(rev. 9/91) and will be accepted at the standard application deadlines
as indicated in the application kit.  The receipt dates for
applications for AIDS-related research are found in the PHS 398 (rev.
9/91) instructions.

FIRST award applications must include at least three sealed letters of
reference attached to the face page of the original application.  FIRST
award applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.

Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
Westwood Building, Room 449, Bethesda, MD 20892, telephone (301)
496-7441.  Section 2 on the face page of the application must be
completed.  Check "YES" to indicate the application is submitted in
response to a program announcement.  The title and program announcement
number must be typed in Section 2a of the application as follows:
"HEMOGLOBIN-BASED OXYGEN CARRIERS:  MECHANISMS OF TOXICITY" PA-93-23.

The completed original application and five legible copies must be sent
or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW CONSIDERATIONS

Although this is an NHLBI PA, the National Institute of Environmental
Health Sciences also has an interest in the subject matter of this PA.
Applications will be assigned to the most appropriate Institute on the
basis of established PHS referral guidelines.  Applications will be
reviewed for scientific and technical merit by study sections of the
Division of Research Grants, NIH, in accordance with the standard peer
review procedures.

Following scientific-technical review, the applications will receive a
second-level review by the appropriate advisory council.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and technical
merit of the proposed grant as determined by peer review, program
needs, balance among research areas of the announcement, and the
availability of funds.

Awards in response to this PA will be made to foreign institutions only
for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.

INQUIRIES

Inquiries regarding this program announcement may be directed to:

Dr. George J. Nemo
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 504
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

For fiscal and administrative matters, contact:

Ms. Jane R. Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A15
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of Federal Domestic Assistance No. 93.839.
Awards will be made under the authority of the Public Health Service
Act, Section 301 (42 USC 241) and administered under PHS grants
policies and Federal regulations, most specifically 42 CFR Part 52 and
45 CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or to Health Systems
Agency review.

$$P3 END ************************************************************

$$P4 BEGIN PA-93-24 *************************************************

VULNERABILITY OF THE OLFACTORY SYSTEM TO THE IMPACT OF ENVIRONMENTAL
TOXICANTS AND PATHOGENS

NIH GUIDE, Volume 21, Number 42, November 20, 1992

PA:  PA-93-24

P.T. 34; K.W. 0705070, 1007003, 1007009, 1002030

National Institute on Aging
National Institute of Allergy and Infectious Diseases
National Institute on Deafness and Other Communication Disorders
National Institute of Environmental Health Sciences
National Institute of Neurological Disorders and Stroke

PURPOSE

The olfactory nerve provides a direct anatomic conduit between the
external chemical environment and the brain.  This location puts the
olfactory system at risk for damage from environmental toxicants and
pathogens.  These toxic agents comprise the major health hazard to
human olfaction.  However, the direct and indirect effects of these
agents on the peripheral and central olfactory system are poorly
understood.  The purpose of this Program Announcement (PA) is to foster
investigator-initiated research fundamental to understanding the impact
of environmental toxicants and pathogens on the olfactory system.  A
broad range of studies extending from the molecular to the behavioral
areas of basic and clinical research is applicable to this PA.  The
scope of these areas encompasses the transport of toxic substances into
the brain through the olfactory nerve; olfactory mucosal defense
mechanisms; neurogenesis; the relation of neurodegenerative diseases,
such as Alzheimer's disease, to olfactory abnormalities induced by
toxic agents; and the vulnerability of an aged olfactory system to
toxic agents.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This PA,
Vulnerability of the Olfactory System to the Impact of Environmental
Toxicants and Pathogens, is related to the priority area of
environmental health.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-11474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-11473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone [phone]).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal Government.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

The mechanisms available for the support of this program are research
project grants (R01) and the First Independent Research Support and
Transition (FIRST) (R29) awards.  Foreign institutions are not eligible
for FIRST (R29) awards.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research Resources
(NCRR) may wish to identify the GCRC as a resource for conducting the
proposed research.  If case, a letter of agreement from either the GCRC
program director or Principal Investigator may be included with the
application.

RESEARCH OBJECTIVES

BACKGROUND

Certain features of the olfactory system are valuable in the study of
some general properties of neural systems and some of these features
provide excellent models for studying the effects of environmental
agents on sensory systems.  For example, the vertebrate olfactory
receptor neuron has become an important neurobiologic model system in
the area of molecular and cell biology for the study of neuronal
plasticity and neuronal development or neurogenesis, including the
developmental steps of cell birth and lineage, differentiation,
synaptogenesis, growth, migration, maturation, and death.  The
olfactory neuroepithelium is unrivaled in its capacity for neuron
replacement and regeneration throughout life.  Receptor neurons of the
main olfactory system (and vomeronasal system) show a remarkable
naturally occurring rate of turnover followed by functional
synaptogenesis and are rapidly replaced following traumatic lesions.
These are the only known projection neurons with this property.
Molecular biologic studies have shown that the maturation process of
regenerating olfactory receptor neurons involves the sequential
expression of several growth associated proteins, such as olfactory
marker protein.  The robust ability of animals to detect and
differentiate odorants has provided a valuable means to gauge the
recovery of olfactory function with behavioral tests after damage to
the receptor neurons.

The olfactory receptor neurons are extremely sensitive to chemical
stimuli, exhibit specific ligand binding, and are the only neurons that
form a direct conduit between the external chemical environment and the
brain.  Uptake of even a small amount of a chemical substance by each
olfactory receptor neuron could have an appreciable effect on the
olfactory bulb because of the magnitude of the receptor neuron input to
the bulb and the high degree of convergence of this input.  These
characteristics make the olfactory system vulnerable to damage from
toxic agents; it has even been suggested that the very process of
chemoreception is damaging to the olfactory receptor neurons.  One of
the most commonly used methods to study olfactory neurogenesis involves
the destruction of certain cells in the olfactory neuroepithelium by
chemicals, including toxicants such as methyl bromide.  The development
of tissue culture methods allows the pharmacologic manipulation of
olfactory plasticity, neurogenesis, and interactions between the
olfactory nerve and olfactory bulb.

The exposed location of the olfactory receptor neurons and their
morphology make them exceptionally suitable for the study of axoplasmic
transport.  Marker substances and precursors can be applied to the
nasal cavity without requiring surgery.  The olfactory nerve consists
of relatively homogeneous population of several million unmyelinated
axons, only a minor fraction of the nerve volume being composed of
glial cells and fibrocytes.  Various organic and inorganic substances,
including dyes, amino acids, colloidal gold, and lectins, can be taken
up by the olfactory nerve and transported to the olfactory bulb.
Videomicroscopic techniques are available to measure organelle movement
during normal conditions and after pharmacologic manipulations.

The olfactory bulb is a model system for the study of neural
organization and plasticity.  For example, repeated stimulation of rat
pups with a specific odorant appears to enhance bulbar neural responses
and may induce a morphological rearrangement of the receptor axon
terminals in the olfactory bulb.  The olfactory bulb is well organized
into distinct laminations that demarcate the local circuits.  The
neurons and synapses that make up these layers have been identified and
well characterized.  Further, the bulb is richly laden with a wide
variety of neuroactive substances.  These properties make the bulb an
ideal physiologic preparation to localize drug and neurotransmitter
receptors and to study the interactions of neurotransmitters with toxic
substances.  The recent application of voltage-sensitive dyes to the
bulb allows simultaneous monitoring of odorant-evoked activity in many
bulbar cells and permits clear interpretation of that activity.  More
recently, in situ hybridization has been used to study the effect of
odor stimulation on c-fos mRNA expression in vertically distributed
aggregates of bulbar neurons.

Several issues related to the impact of toxic agents on the olfactory
system are mentioned below.  A fundamental issue is the degree to which
genetic and environmental factors affect human olfaction over the
lifespan and regulate olfactory neurogenesis.  Human olfactory function
is known to decrease with age.  Several studies in humans suggest that
the olfactory mucosa is replaced with respiratory mucosa as a result of
frequent infectious diseases of the nasal chambers, exposure to toxic
chemicals, head injury, or age-related conditions.  Continued mitosis
in the olfactory neuroepithelium may be under the programmed genetic
control of a biological clock.  However, the longevity of an olfactory
cell can be readily modified or manipulated by environmental factors,
both in nature and in the laboratory.

Olfactory perireceptor events have also recently received attention.
The identification of odorant binding proteins has generated interest
in the influence of the composition and physical properties of
olfactory mucus secretions on the access of odor molecules to receptor
sites on olfactory receptor neurons, odorant binding, and clearance
from the vicinity of these sites.  The human olfactory mucosa is a site
for synthesis and secretion of immune, antimicrobial, and other defense
factors against pathogens.  Although immunocytochemical studies have
shown that the olfactory mucosa contains highly active enzyme systems,
such as cytochrome P450, for metabolizing xenobiotics, including
odorants, xenobiotic metabolism in the olfactory system has received
little attention.

Issues regarding the transport of toxic agents into the olfactory
system have important implications for public health.  Some viruses are
transported from the olfactory neuroepithelium to the olfactory bulb
and then spread into the rest of the brain.  According to some
investigators, the olfactory deficits expressed in the early stages of
Alzheimer's disease and Parkinson's disease may result from substances
that entered the brain through the olfactory nerve.  Some investigators
have reported morphological and immunocytochemical abnormalities of the
olfactory neuroepithelia in patients with Alzheimer's disease and
Parkinson's disease.

The effects of environmental toxicants and pathogens on the olfactory
system are complex and poorly understood.  Studies of these effects are
of great ecologic importance.

Research Goals and Scope

The ultimate goal of this research program to develop targeted drug
delivery, vector-based vaccines, and other interventions for the
treatment and prevention of the effects of toxic agents on the
olfactory system.  Collaboration is encouraged between investigators
within and outside of the field of olfaction, including inhalation
toxicologists, virologists, immunologists, and molecular biologists.
A broad range of studies extending from the molecular to the behavioral
levels of basic and clinical research is applicable to this
Announcement.  Topics might include some of those listed below.
Investigators are encouraged to consider other topics relevant to this
program.

o  For any suspected toxicant or pathogen, evidence of the causal
relationship to observed findings of damage to the olfactory system.

o  Neurophysiologic and histopathologic studies that determine the
localization of damage in the olfactory system.

o  Olfactory abnormalities induced by toxic agents as early signs of
neurodegenerative diseases, such as Alzheimer's disease and
Parkinson's disease.

o  Specific anosmias induced by toxic agents.

o  Age-related changes in chemosensory responses to toxic agents.

o  Investigations into the molecular mechanisms initiated by toxic
agents.

o  Defense mechanisms of the olfactory system against the direct and
indirect effects of toxic agents; the role of supporting cells in
phagocytosis and other defense responses; and the role of Bowman's
glands.

o  The role of xenobiotic metabolism in the peripheral and central
olfactory system; biotransformation of a substance to a less or more
toxic substance and biotransformation of a nonodorous substance into an
odorous one; synergisms between toxic agents; and site-specific
metabolism.

o  Active and passive mechanisms of uptake of toxic agents into the
olfactory neuroepithelium.

o  Effects of toxic agents on stem cells and other cell populations of
the olfactory neuroepithelium; neurogenesis of olfactory receptor
neurons; trophic and tropic interactions between the olfactory nerve
and the olfactory bulb; and olfactory bulb neurochemistry and glial
cells.

o  Anterograde and retrograde axoplasmic transport of toxic agents in
the olfactory nerve; impact of transport on neurogenesis; routing of
proteins to specialized regions of the plasma membrane; and native
mitochondrial synthesis and import of proteins in mitochondrial
biogenesis.

o  Transneuronal transport of toxic agents from the olfactory bulb to
other parts of the brain.

o  Comparison of the effects of toxic agents on olfaction with the
effects on other chemosensory systems.

o  Interactions between the effects of nutrients and toxic agents on
the olfactory system.

o  Mechanisms of regeneration, repair, or plasticity following
administration of toxic agents; use of implantation of tissues to
enhance these processes.

o  Development of more specific and sensitive tests for detecting early
damage by toxic agents to the olfactory system; identification of
naturally occurring models; and development of new animal models of
neuronal regeneration and repair using paradigms involving damage to
the olfactory system by toxic agents.

o  Potential of the olfactory nerve for administration of
pharmacotherapeutics to combat the effects of toxic substances on the
olfactory system.

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS.

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 in Sections 1-4
of the Research Plan AND summarized in Section 5, Human Subjects.
Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However, NIH
recognizes that it may not be feasible or appropriate in all research
projects to include representation of the full array of United States
racial/ethnic minority populations diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities. If the required information is not contained within the
application, the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398
(rev. 9/91) and will be accepted at the standard application deadlines
as indicated in the application kit.

Application kits are available at most institutional offices of
sponsored research and may be obtained from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
Westwood Building, Room 449, Bethesda, MD 20892, telephone
301/496-7441.   The title and number of the announcement must be typed
in line 2a on the face page of the application.

FIRST award applications must include at least three sealed letters of
reference attached to the face page of the original application.  FIRST
award applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.

The completed original application and five exact copies must be sent
or delivered to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

REVIEW PROCEDURES

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be reviewed for scientific and technical
merit by study sections of the Division of Research Grants, NIH, in
accordance with the standard NIH peer review procedures.  Following
scientific-technical review, the applications will receive a
second-level review by an appropriate national advisory council or
board.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:

o  Quality of the proposed project as determined by peer review
o  Program balance among research areas of the announcement
o  Availability of funds

INQUIRIES

Direct inquiries regarding the major areas of research interest in this
program to:

Chemoreception

Jack Pearl, Ph.D.
Division of Communication Sciences and Disorders
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400B
Rockville, MD  20892
Telephone:  [phone]
FAX:  [phone]

Age-related disorders

Deborah L. Claman, Ph.D.
Neuroscience and Neuropsychology of Aging
National Institute on Aging
Gateway Building, Suite 3C307
Bethesda, MD  20814
Telephone:  [phone]
FAX:  [phone]

Infectious diseases

David Klein, Ph.D.
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A10
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

Neurotoxicology of environmental toxicants/pollutants

Annette Kirshner, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Box 12233, MD 3-02
Research Triangle Park, NC  27709
Telephone:  [phone]
FAX:  [phone]

Neural plasticity and axonal regeneration

Mary Ellen Michel, Ph.D.
Division of Stroke and Trauma
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8A13
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

Direct inquiries regarding fiscal matters:

Sharon Hunt
Division of Extramural Activities
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400B
Rockville, MD  20892
Telephone:  [phone]
FAX:  [phone]

Joseph Ellis
National Institute on Aging
Gateway Building, Suite 2N212
7201 Wisconsin Avenue
Bethesda, MD  20814
Telephone:  [phone]
FAX:  [phone]

Todd Ball
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B35
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

Carolyn Winters
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Box 12233, MD 2-01
Research Triangle Park, NC  27709
Telephone:  [phone]
FAX:  [phone]

Dwight Mowery
Division of Extramural Activities
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

AUTHORITY AND REGULATIONS

The programs of the NIA, NIAID, NIDCD, NIEHS, and NINDS are identified
in the Catalog of Federal Domestic Assistance, Nos. 93.173, 93.866,
93.856, 93.113, and 93.854, respectively.  Awards are made under
authorization of the PHS Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR
Part 74.  This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.

$$P4 END ************************************************************


$$XID RFA DK9311 DK-93-11 P1O1 *****************************************

VANADIUM SALTS IN THE CLINICAL TREATMENT OF DIABETES MELLITUS

NIH GUIDE, Volume 21, Number 42, November 20, 1992

RFA:  DK-93-11

P.T. 34; K.W. 0715075, 0740020, 0755015, 0765020, 1007009

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  February 18, 1993
Application Receipt Date:  March 17, 1993

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) invites investigator-initiated research grant applications to
study the effects of vanadium salts as potential therapeutic agents for
the treatment of diabetes mellitus.  A significant amount of prior
research in experimental animals, isolated tissues, and cell
preparations has strongly suggested that various forms of vanadium have
a beneficial impact on the abnormal metabolic state associated with
this disease.  This solicitation intends to support preliminary studies
of efficacy, dosimetry, and toxicity in human subjects with diabetes.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Vanadium Salts in the Clinical Treatment of
Diabetes Mellitus, is related to the priority area of diabetes and
chronic disabling conditions.  Potential applicants may obtain a copy
of "Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1). through the Superintendent
of Documents, Government Printing Office, Washington, DC 20402-9325
(telephone [phone]).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit or
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.  Minority
individuals and women are encouraged to submit as Principal
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01).  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.
The total project period for applications submitted in response to the
present RFA may not exceed two years.  The anticipated award date is
September 30, 1993.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated
applications and be reviewed according to the customary peer review
procedures.

In order to adhere to prudent principles of cost-containment, requested
direct costs must not exceed $160,000 per year for any single
application.  Applications exceeding this limit will not be reviewed as
part of this RFA.  With respect to post-award administration, the
current policies and requirements that govern the research grant
programs of the NIH will prevail.

FUNDS AVAILABLE

A total of up to $500,000 in first year and $500,000 in the second year
will be committed by the NIDDK to fund applications submitted in
response to this RFA.  The NIDDK plans to make one to three awards in
FY 93 contingent on the receipt of highly meritorious applications in
response to this solicitation.  The award of grants pursuant to this
RFA is contingent on the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

The term "diabetes mellitus" encompasses a group of disorders
characterized by abnormal metabolism of carbohydrates, lipids, and
proteins.  The classical clinical manifestations of diabetes include
chronic elevations of blood glucose levels and a defined constellation
of long-term sequelae.  Two major forms of diabetes are recognized.
Insulin-dependent diabetes mellitus (IDDM) is the result of the
virtually total destruction of the insulin-producing beta cells of the
pancreas, usually by an autoimmune process of still obscure
pathogenesis.  The existing treatment of this form of diabetes requires
insulin replacement therapy.  Non-insulin-dependent diabetes mellitus
(NIDDM) appears to be the result of both significant resistance by the
relevant tissues to the action of insulin and the coincident inability
of the pancreatic beta cells to sufficiently compensate for this
resistance by increasing secretion.  Current treatment for this form of
diabetes includes lifestyle modification (i.e., diet, exercise, weight
loss) to ameliorate insulin resistance, oral hypoglycemic agents to
stimulate insulin secretion and perhaps improve insulin resistance, and
insulin replacement therapy, if necessary.

Vanadium, a trace metal for a broad range of organisms, including
humans, has been postulated to be a co-factor for a number of enzymatic
processes.  Salts of this element have been known for a decade to
inhibit the action of a number of phosphatases in vitro.

In particular, vanadate has been used frequently in laboratory settings
with isolated tissues and cell cultures as a tool in biochemical
studies of the mechanisms of insulin action and experimental insulin
resistant states.  This ion has shown insulinmimetic properties in
preparations of muscle, liver, and adipose tissue as well as whole
animals with various forms of diabetes.  Non-diabetic laboratory
animals appear to show much less response.

Initial hypotheses to explain this property of vanadate centered around
inhibition of tyrosine phosphatase activity associated with the
membrane-bound insulin receptor.  Although such inhibition occurs, this
does not appear to adequately account for the actions of vanadate to
induce insulin-like responses.  Several research groups are presently
exploring possible post-receptor mechanisms for a definitive answer to
this question.

Despite the lack of consensus on the precise biochemical mechanism of
action for vanadate, it is clear that a broad array of cellular and
physiologic processes are modified in an insulinmimetic pattern.  These
include glycemia, transmembrane glucose transport, glucose utilization,
glycolysis, gluconeogenesis, glycogen metabolism, fatty acid and lipid
metabolism, and bile acid metabolism in a number of different
laboratory preparations and models of diabetes.  The magnitude and
universality (i.e., across tissues, across species, across diabetes
type or model) of these effects are still being debated in the
literature.  In addition, vanadium can exist in a number of oxidation
states (both cationic and anionic) and the state most relevant to
insulin action is not established.

Before embarking on human studies, it will be important to consider the
known and potential toxicities of vanadium.  There is a growing
literature on the toxicology of this heavy metal which has been
identified as a pollutant byproduct of coal combustion with significant
health risks.

Most of this work concerns the impact of pulmonary exposure through
aerosols, but systemic effects after absorption have been documented in
the kidney, bone, and blood cells.  The oxidative state of vanadium may
relate to toxicity, with some ions being less detrimental.  Therefore,
clinical studies of any vanadium compound with regard to diabetes will
need to carefully monitor for incipient toxicity.

Scope

The objective of this RFA is to stimulate investigator-initiated
research designed to provide feasibility data on the clinical utility
of vanadium-containing compounds for the treatment of diabetes mellitus
in humans.  Therefore, all applications in response to this RFA must
primarily concern the clinical study of patients with this disease
(NIDDM and/or IDDM) and may include normal (non-diabetic) volunteers as
appropriate to the experimental design.  Relevant research topics
listed below are examples and should not be construed as required or
limiting.  Responsive applications to this solicitation include:

o  placebo controlled, double-blind comparisons of alternative
treatments with vanadium salts for diabetes mellitus

o  assessment of metabolic effects of vanadium salts in human subjects
including dose-response relationships

o  studies of therapeutic combinations including vanadium salts

o  toxicologic assessments of oral vanadium salts in humans with
diabetes

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women in
study populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of minorities
and women in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males and females of all ages.  If women or minorities are excluded or
inadequately represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research design
and sample size appropriate for the scientific objectives of the study.
This information must be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan and summarized in Section 5, Human
Subjects.  Applicants are urged to assess carefully the feasibility of
including the broadest possible representation of minority groups.
However, NIH recognizes that it may not be feasible or appropriate in
all research projects to include representation of the full array of
United States' racial/ethnic minority population (i.e., Native
Americans [including American Indians or Alaskan natives],
Asian/Pacific islanders, blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology, prevention
(and preventive strategies), diagnosis, or treatment of disease,
disorders or conditions, included, but not limited to, clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the Unites States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the selected
study population is inadequate, it will be considered a scientific
weakness or deficiency in the study design and reflected in assigning
the priority score to the application.

All applications for clinical research submitted to NIH are required to
address these policies.  NIH funding components will not award grants
or cooperative agreements that do not comply with these policies.

LETTER OF INTENT

Potential applicants are strongly encouraged to submit a letter of
intent by February 18, 1993.  The letter of intent is to include: (1)
name of the Principal Investigator/program director, and principal
collaborators, (2) descriptive title of the potential application, (3)
identification of the organization(s) involved, and (4) the number and
title of the RFA in response to which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of a subsequent application, the information
that it contains allows NIDDK staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:,

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of Grants
Inquiries, Division of Research Grants, National Institutes of Health,
5333 Westbard Avenue, Room 449, Bethesda, MD  20892, telephone
301/496-7441; and from the NIDDK program administrator named below.

The RFA label found in the form PHS 398 application kit must be affixed
to the bottom of the face page of the original completed application
form.  Failure to use this label could result in delayed processing of
the application such that it may not reach the review committee in time
for review.  In addition, the RFA title, "Vanadium and Clinical
Diabetes," and number, "DK-93-11," must be typed on line 2a of the face
page of the application form, and the YES box must be marked.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center of Research Resources
may wish to identify the Center as a resource for conducting the
proposed research.  If so, a letter of agreement from the GCRC Program
Director should be included in the application material.

Applications must be received by March 17, 1993.  If an application is
received after this date, it will be returned to the applicant without
review.  Submit a signed original of the application, including the
Checklist, and three signed photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney
Westwood Building, Room 605
Bethesda, MD  20892

The Division of Research Grants (DRG) will not accept any application
in response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG will not accept any application that is
essentially the same as one already reviewed. This does not preclude
the submission of substantial revisions of the applications already
reviewed, but such application must include an introduction addressing
the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the DRG
and responsiveness by the NIDDK. Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, NIDDK staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
application at the next review cycle.

Applications may be triaged by an NIDDK peer review group on the basis
of relative competitiveness.  The NIDDK will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and Institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are complete
and responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIDDK.  The second level of review will be
provided by the National Diabetes and Digestive and Kidney Diseases
Advisory Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications.

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly, but not exclusively, in the area of the
proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research.

AWARD CRITERIA

The anticipated date of award is September 30, 1993. The following will
be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Programmatic priorities of the NIDDK

INQUIRIES

Inquiries regarding programmatic issues related to this announcement
may be directed to:

Joan T. Harmon, Ph.D.
Executive Director, Diabetes Research Program
Diabetes Programs Branch, DDEM
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 622
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

Inquiries regarding fiscal matters may be directed to:

Betty Bailey
Grants Management Specialist
Grants Management Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  [phone]
FAX:  [phone]

Schedule:

Letter of Intent:               February 18, 1993
Application Receipt Date:       March 17,1993
Initial Review:                 June/July 1993
NIDDK Advisory Council Review:  September 1993
Anticipated Award Date:         September 30, 1993

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.847.  Awards are made under the authority of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public
Law 99-158, 42 USC 241 and 285) and administered under PHS grants
policies and federal regulations 42 CFR Part 52 and 45 CFR Part 74.
This program is not subject to the intergovernmental review
requirements of Executive Order 12372 or Health Systems Agency review.