VULNERABILITY OF THE OLFACTORY SYSTEM TO THE IMPACT OF ENVIRONMENTALTOXICANTS AND PATHOGENS NIH GUIDE, Volume 21, Number 42, November 20, 1992 PA: PA-93-24 P.T. 34 Keywords: Sensory System Environmental Effects Toxicology Neuroscience 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 202-783-3238). 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: (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 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. .
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