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

PA:  PA-93-24

P.T. 34


  Sensory System 

  Environmental Effects 



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


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.


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 202-783-3238).


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.


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




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


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


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


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


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


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


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.




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


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.


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


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**


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



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding


o  Quality of the proposed project as determined by peer review

o  Program balance among research areas of the announcement

o  Availability of funds


Direct inquiries regarding the major areas of research interest in this

program to:


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:  (301) 402-3464

FAX:  (301) 402-6251

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:  (301)496-9350

FAX:  (301) 496-1494

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:  (301) 496-5305

FAX:  (301) 496-8030

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:  (919) 541-0488

FAX:  (919) 541-2860

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:  (301) 496-4226

FAX:  (301) 480-1080

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:  (301) 402-0909

FAX:  (301) 402-1758

Joseph Ellis

National Institute on Aging

Gateway Building, Suite 2N212

7201 Wisconsin Avenue

Bethesda, MD  20814

Telephone:  (301) 496-1472

FAX:  (301) 402-0066

Todd Ball

Division of Extramural Activities

National Institute of Allergy and Infectious Diseases

Solar Building, Room 4B35

Bethesda, MD  20892

Telephone:  (301) 496-7075

FAX:  (301) 496-3780

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:  (919) 541-7823

FAX:  (919) 541-2860

Dwight Mowery

Division of Extramural Activities

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

Bethesda, MD  20892

Telephone:  (301) 496-9231

FAX:  (301) 402-0219


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.


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