EXPIRED
GENE/ENVIRONMENT INTERACTION IN NEURODEGENERATIVE DISEASE RELEASE DATE: August 6, 2003 PA NUMBER: PAS-03-160 (Expiration date changed, see NOT-ES-06-006) (see NOT-ES-04-009) EXPIRATION DATE: March 2, 2006, unless reissued. National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.113, 93.115 THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Background o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA There is provocative evidence that environmental exposures to certain neurotoxicants (heavy metals, pesticides and fungicides) may play a role in the development of neurodegenerative movement disorders such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Recent research in these diseases has focused on both the underlying biological processes critical to disease manifestation for the development of new treatments and on the relative roles of environmental, endogenous neurochemical and genetic factors in their etiologies. Much work, however, remains to be done to clarify these fundamental processes. The objective of this three-year Program Announcement (PA) is to stimulate research on the relative roles of environmental, endogenous neurochemical and genetic factors in the causation of neurodegenerative diseases. In previous years, the NIEHS has focused its efforts on the expansion of research in Parkinson's disease culminating in the establishment of Collaborative Centers for Parkinson's Disease Environmental Research (See http://www.niehs.nih.gov/dert/consorti.htm) This new initiative will selectively shift its research focus each year to emphasize a different neurodegenerative disease. In the current year, the special focus is to mainly solicit research on gene-environment interactions as a risk factor in ALS (a fatal disease of unknown etiology marked by the progressive degeneration of motor neurons) in order to stimulate much needed research in this area. In succeeding years, there will be an announcement indicating a different neurodegenerative disease focus area. Background Several epidemiological studies have implicated gene/environment interactions in the development of PD and ALS. Nevertheless, it is still not clear whether differences in prevalence rates or clusters of these diseases in various communities are due to the differential distribution of a hypothetical environmental toxicant or are more frequent where a familial heritable defect is more common. To date, analytic epidemiological studies have varied in case and control selection methodology and venues (e.g., clinics, population bases, different countries) partly accounting for the disparate conclusions reached by some investigators. While a good deal of research has been devoted to the influence of the environment in the susceptibility to PD, there has not been a similar effort committed to ALS. In ALS the motor neurons of the brain and spinal cord are primarily targeted to degenerate, leading to muscle atrophy and progressive paralysis while cognitive function is usually unimpaired. No treatment is currently available that will prevent, reverse, or otherwise alter the course of the disease nor are the basic pathogenetic mechanisms of the disease known. On a worldwide basis, ALS affects five to seven persons per 100,000, striking about 1.2 times as many men as women. Around 30,000 Americans have ALS. About 10 percent of all cases are believed to be familial, usually inherited in an autosomal dominant pattern, and affecting roughly half of family members. Prevalence studies indicate about 5,000 new cases of ALS in the U.S. each year, 90 percent of which are sporadic. Familial and sporadic ALS (SALS) appear to be clinically undistinguishable. The disease commonly strikes in the fifth through seventh decades of life, although cases in young adults and in the elderly are known. The average duration of life after onset of symptoms of ALS is around three years, encompassing a progressive course of increasing disability. RESEARCH OBJECTIVES Some progress has been made in recent years toward understanding the biological bases of ALS. A number of pathological, biochemical, and electrophysiological abnormalities are found in affected patients and are seen in post-mortem nervous tissues. Markers for genes in familial ALS (FALS), both dominant and recessive, have been identified, but they represent only a portion of the possible gene loci. Fifteen to 20 percent of FALS have a mutation of the copper/zinc superoxide dismutase (SOD1) gene on chromosome 21. However, the overwhelming majority of ALS patients do not have this mutation. Genetic studies of ALS linked to other chromosomes are needed especially of those genes easily influenced by neurotoxicants. It is significant that the first descriptions of ALS coincided with the industrial revolution. Therefore, it has been logical to consider whether environmental contamination associated with increased levels of industrial activity might be implicated in its pathogenesis. The possible role of occupational exposures in ALS has also been investigated. Epidemiological studies have implicated heavy metals and other environmental exposures as risk factors for ALS but as yet have not provided a clear directional lead. For example, various studies have looked at occupational exposure to lead, mercury, selenium, manganese, aluminum, and iron exposure in assessing risk factors for the disease. Calcium has also been studied because of suggestions that excitotoxicity and calcium channel antibodies may be implicated in its etiology. In addition, in some areas, agricultural workers seem to have a higher risk of developing ALS, while studies on the exposure to industrial solvents and chemicals have brought mixed results. No coherent picture has emerged from these studies nor have many of them been correlated with genetic studies. Therefore, much remains to be learned about the mechanisms through which genetic mutations and other biological insults lead to pathology. Consequently, research on the response to endogenous and environmental toxicants, on the abnormal biology of the affected motor and non-motor neurons, and on the identification of metabolic, endocrine, and immunological abnormalities needs to be expanded. The genetic defects identified in the familial form of ALS have lead to the development of some useful animal models of the disease but more models are needed to expand research on the abnormal biology of the affected motor neuron and nonneuronal cells, on nervous system response to endogenous and environmental toxins and toxicants, and on identification of metabolic, endocrine, and immunological abnormalities. Several meetings focused on ALS have categorized fruitful mechanistic approaches to studying ALS. These are (1) the role of mitochondrial oxidative stress, (2) the role of calcium/excitotoxicity, (3) the role of proteosomal dysfunction and (4) the role of cytoskeletal dysfunction. Additional research is also needed to understand the contribution of environmental exposure, endogenous susceptibility factors, and increasing age in the disease linkage. This will require a concurrent advancement and refinement of methodologies and sciences. Of particular significance may be those approaches that can be used across species from lower animals to humans. Such approaches permit a precise characterization in animal models of alterations arising from defined environmental exposures that can serve as a cogent guide to underlying cellular and molecular mechanisms in humans. This initiative will seek to solicit novel approaches to understanding ALS, with emphasis on how gene-environment interactions may play in the above. Examples of research goals that could be pursued, especially in appropriate animal models and tissue culture, are listed below. o Development of animal models of ALS especially nonmammalian models useful for gene/environment research. o Development of biomarkers of exposure/disease in animal models (metabonomics, etc.) o Research on modifier genes and environmental influences in animal models. o Studies on the intersections/synergies between genetic susceptibilities and environmental factors, as well as strategies for identifying putative toxicants and other environmental factors involved in the etiology of ALS. o Establishment of disease incidence and variation according to age, gender, race/ethnicity, geography, exposure. o Studies on potentially informative clusters (Western Pacific ALS/PDC, Persian Gulf War ALS, Kelly Air Force, etc.) o Studies on occupational/environmental exposures and non-occupational exposures (evidence for role of metals, pesticides, solvents, residential/avocational exposures, tobacco, alcohol, infectious agents.) o Research on the potential role of dietary excitotoxins in Western Pacific ALS-PDC-Dementia; analogies with other disorders. o Research on the role of dietary intake of antioxidants, minerals (copper, zinc, iron) and the association of fat and fiber intake with ALS. o Research on factors targeting putative environmental toxicants specific to motor neurons and surrounding cells including muscle cells. o Research on disease mechanisms on cellular/subcellular level (oxidative stress, excitotoxicity, apoptosis) from neurotoxic exposures. o Evaluation of retrograde axonal transport of toxins to the spinal motor neurons and their response (access and possible uptake of toxic substances at the neuromuscular junction.) The above is not intended to be all-inclusive. Moreover, the NIEHS would like to encourage multidisciplinary and interdisciplinary studies. What may be especially useful are collaborations with ongoing research in other motor disorder diseases that could be expanded to include ALS studies. We also encourage the use of novel animal models such as drosophila, zebra fish and C. elegans, as well as newly available technologies. Especially useful would be collaborative pooling of resources to standardize epidemiological instruments, microarray analyses, -omics technologies, etc, for meaningful use among several laboratories. MECHANISM(S) OF SUPPORT This PA primarily will use the NIH Research Project Grant (R01) and Exploratory/Developmental Grant (R21) award mechanisms (though, if appropriate, competitive supplements may be considered if it is to accomplish collaborations.) As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. This PA uses just- in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. FUNDS AVAILABLE The NIEHS intends to commit approximately $2M in FY 2004 to fund 10-15 new grants in response to this PA. An applicant may request a project period of up to five years for R01s and up to two years for R21s. Direct costs for R21s may not exceed $275,000. The characteristics, requirements, preparation, and review criteria for R21 applications are described at http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIEHS provide support for this program, awards pursuant to this PA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Annette Kirshner, Ph.D. Program Administrator Cellular, Organs and Systems Pathobiology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD-23 Research Triangle Park, NC 27709 Telephone: (919) 541-0488 FAX: (919) 541-5064 Email: kirshner@niehs.nih.gov o Direct your questions about financial or grants management matters to: Pamela Evans Grants Management Specialist Grants Management Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences P.O. Box 12233, MD-22 Research Triangle Park, NC 27709 Telephone: (919) 541-7629 FAX: (919) 541-2860 Email: evans3@niehs.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least six weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institutes of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Environmental Health Sciences Council. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate, the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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