This Program Announcement expires on July 1, 2003, unless reissued. MOLECULAR GENETICS OF DRUG ADDICTION VULNERABILITY Release Date: June 27, 2000 PA NUMBER: PA-00-115 National Institute on Drug Abuse THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE This Program Announcement (PA) seeks investigator-initiated applications for research projects that identify chromosomal loci and genetic variation in genes that are associated with increased vulnerability to addiction or dependence on stimulants (e.g., cocaine and amphetamine), narcotics (e.g., opiates), nicotine, benzodiazepines, barbiturates, cannabis, hallucinogens, and/or multiple drugs of abuse in human beings. Thus, applications examining the genetics of addiction vulnerability to both illicit and legal drugs of abuse are relevant to this PA. This program announcement is a continuation of the program initiated by RFA DA-99-003, "Genetics of Drug Addiction Vulnerability," http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-99-003.html. For other NIDA funding opportunities in genetics see the NIDA Genetics Workgroup homepage http://www.drugabuse.gov/about/organization/Genetics/about_genworkgroup/index.html. 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, Genetics of Drug Addiction Vulnerability, 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/. 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. The collection of clinically well characterized samples of sufficient size for linkage analyses and for linkage disequilibrium mapping studies in genetically isolated populations may be facilitated by the establishment of international consortia. Collaborations among U.S. scientists and scientists at foreign institutions are encouraged, when scientifically appropriate. In these cases, awards may be made to foreign institutions or to domestic applications that include foreign components. Foreign institutions are not eligible for program project (P01) grants. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) regular research project (R01) grant, and a program project (P01) grant mechanism. The P01 mechanism supports broadly based multidisciplinary research programs that have a well defined, central research focus or objective. The P01 consists of a minimum of three interrelated individual research projects that contribute to the overall program objective. To achieve sufficient statistical power or needed expertise these projects may be located at more than one institution. This type of award can also provide support for certain shared resources ( cores ) that provide funds for tasks common to two or more projects within the award. NIH limits the time period for P01 grants to 5 years. Modular instructions apply only to R01 applications. The cover letter and abstract should indicate the type of mechanism for which the applicant is applying. Specific information on individual research mechanisms can be obtained from the NIDA web site for funding information at http://www.nida.nih.gov/Funding.html. 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. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. RESEARCH OBJECTIVES Background Evidence from adoption and twin studies, from genetic strains of rodents, and from induced mutations in mice, suggests that heritability may play a role in vulnerability to addiction. The genetic variants underlying increased vulnerability to drug addiction are unknown. However, new scientific opportunities may now make it possible to identify and characterize the genetic variants that contribute to addiction vulnerability. This knowledge will improve diagnosis, prevention, and treatment of drug addiction. By better understanding the genetic factors involved in the addiction process, the environmental contributions to this disease can also be better understood. Recent advances in statistical genetics, molecular biology, and genomic approaches have greatly accelerated the ability to identify the etiology of diseases that have a genetic basis. The power of the genetic approach for neuroscience is evidenced by the recent positional cloning of genetic variations associated with many cases of Alzheimer"s disease and rare forms of Parkinson"s disease. Animal models of these genetic disorders are now being created using transgenic technology. These models provide a greater understanding of the underlying biology of the disease. These and related approaches are likely to have applicability to the brain disease of addiction, even though there is not any evidence that addiction follows a strictly Mendelian pattern of inheritance in humans. The challenge for the molecular genetics of addiction, like many other complex genetic disorders lacking simple patterns of Mendelian inheritance in humans, is addressing the complexity of polygenic disorders with substantial environmental influences. Continued advances during the next 5-10 years will enhance the study of the molecular genetics of addiction vulnerability. Research Scope and Goals This PA encourages applications for research projects that identify chromosomal loci and variation in genes that are associated with increased vulnerability to addiction. Genetic approaches may include but are not limited to linkage, linkage disequilibrium, and association studies. Data may be collected from the general population, population isolates, and/or recent admixed populations. Standard and novel methods of analysis for the identification of genetic variation conferring vulnerability to a complex genetics disorder such as drug addiction are highly encouraged. Investigators may include, as a component of their project, non-human models to study the genetics of addiction vulnerability. Phenotype definition of both affected and unaffected individuals is a central issue in the analysis of complex traits such as addiction. The use of phenotypes defined by quantity-frequency criteria and diagnostic criteria (such as the DSM-III-R or DSM-IV criteria) that have been shown to have significant heritability in twin and/or adoption studies is strongly encouraged. For diagnostic purposes, there are numerous structured or semi- structured assessment instruments with high diagnostic reliability, including the Structured Clinical Interview for DSM-III-R or IV (SCID), the Psychiatric Research Interview for Substance and Mental Disorders (PRISM), the Structure Clinical Assessment for Neuropsychiatry (SCAN), the Composite International Diagnostic Interview (CIDI), the CIDI-Substance Abuse Module (CIDI-SAM), the Diagnostic Interview Schedule (DIS), and the Alcohol Use Disorder and Associated Disabilities Interview Schedule (AUDADIS). However, alternative phenotype definition may better describe the genetic aspects of addiction. Therefore, investigators may propose the use of other phenotype markers such as the presence or absence of biological markers or exhibition of unique individual traits, as well as combinations of these or co-morbid condition. In addition, the use of advanced analytical methods such as principal-components analysis, discriminant analysis, or artificial neural networks may help define groups of phenotypes with a higher heritability for complex traits. Identifying specific genes that mediate addiction or other complex, multi- genic diseases is complicated by the fact that analytical methods developed for single-gene disorders do not necessarily incorporate the effects of gene interactions. Investigators are encouraged to consider using innovative genetic models, pedigree structure, and methods of statistical analysis for the identification of genetic variations conferring vulnerability to a complex genetics disorder such as drug addiction. Data from laboratory, field and clinical research is beginning to show gender differences in biological factors in drug abuse, the progression and initiation to drug use and abuse, the antecedents and consequences of drug use and abuse, and prevention and treatment. Examination of gender differences in the molecular genetics of addiction vulnerability is highly encouraged. The NIDA Genetics Consortium (NGC) The nucleus of the NIDA Genetics Consortium (NGC) are investigators who were awarded grants under the RFA, "Genetics of Drug Addiction Vulnerability" (DA- 99-003) as well as those who have modified their projects to conform to the guidelines listed in that RFA to use the resources provided by the NIDA Center for Genetics Studies. The NIDA Center for Genetics Studies is funded by a contract awarded to Rutgers University with a subcontract to Washington University for the purpose of creating databases, cell lines, and DNA samples, and for wide distribution of the data and DNA to the scientific community. After a proprietary period, the NIDA Center for Genetics Studies will, upon proper application and approval, distribute both the data and DNA samples to qualified researchers. Members of the NGC meet two to three times a year to discuss issues related to the molecular genetics of addiction vulnerability. Investigators belonging to NGC have developed detailed plans for the dissemination and distribution of all clinical, diagnostic, and pedigree information, as well as the generation of cell lines and the distribution of DNA, 12-18 months after the funding period. As part of the sharing plan, the investigators belonging to the NGC agree to send blood samples from study subjects and specific diagnostic and descriptive data to a repository (NIDA Center for Genetics Studies). These specific diagnostic and descriptive data include 1) subject ID #, 2) family ID #, 3) site ID #, 4) parental ID #s, 5) sex, 6) death status, 7) ethnicity or geographic origin of ancestry, 8) age and/or year of birth, 9) twin status, 10) DSM-III-R diagnoses, 11) DSM-IV diagnoses, 12) instrument used to establish diagnoses, 13) answers to all of the questions in the structured interview or, minimally, the answers to those questions from which the addiction diagnoses were established, 14) age of onset of drug dependence and quantity-frequency of peak lifetime use of all addictive substances, and 15) Proband. Applicants responding to this announcement are strongly encouraged to join the NGC. Applicants wishing to join the NGC are expected to follow the stipulations under special requirements in the RFA "Genetics of Drug Addiction Vulnerability" http://grants.nih.gov/grants/guide/rfa-files/RFA-DA-99-003.html and to seek the advice of program staff. By joining the NIDA Genetics Consortium the applicant will: o Increase statistical power of the samples being collected, o Enhance quality control of the data collected, o Facilitate and enhance opportunities for collaboration, o Have access to a data management facility to create extensively documented files at no cost, o Have high quality cell lines produced upon receipt of blood samples, o Have aliquots of high quality DNA extracted from the cell lines and returned at no cost, o Have an unlimited supply of DNA, and o Be able to devote more resources to data collection and data analysis. Investigators with a currently funded NIH grant with specific aims related to the genetics of addiction who would like to join the NIDA Genetics Consortium should also contact the program official listed at the end of the announcement. Available Genotyping Resources Investigators should note that an existing resource available to investigators for genotyping is the Center for Inherited Disease Research (CIDR), which is supported by a contract to Johns Hopkins University by eight NIH institutes including NIDA. CIDR was established in 1996 to provide high- throughput genotyping and statistical services for complex genetic diseases to the scientific community at large. Introductory no cost access to CIDR resources is available to investigators who have been approved by the CIDR Access Committee (CAC) and who are supported by one of the eight supporting NIH institutes (including NIDA). Thus, projects supported by this PA are eligible for no cost access to CIDR resources following CAC approval. Investigators should request access to CIDR resources, if needed, and obtain CIDR approval before the requested start date of the grant. The deadlines for submission of applications requesting CIDR access are November 1, February 1, and June 1. For more information about CIDR, see the CIDR Web site at http://www.cidr.jhmi.edu or contact Dr. Jerry Roberts at 301-402-0838 or at jerry_roberts@nhgri.nih.gov. Alternatively, investigators may wish to use the Mammalian Genotyping Service (http://research.marshfieldclinic.org/genetics/default.htm) at the Marshfield Medical Research Foundation in Marshfield, Wisconsin. This facility is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) at NIH and is provided at no cost to investigators whose projects are approved for genotyping by the Scientific Advisory Panel of the Mammalian Genotyping Service. For submission dates, investigators should contact the Mammalian Genotyping Service at (715) 387-9150. DATA SHARING PLAN: DISSEMINATION OF DATA AND BIOLOGICAL MATERIALS The sharing of biological materials, interview and other assessment data, and genotype information (including software) in a timely manner has been an essential element in the rapid progress that has been made in the genetic analysis of human diseases. PHS policy is that investigators must make unique research resources readily available for research purposes to qualified individuals within the scientific community when first results based on these resources have been published (PRINCIPLES AND GUIDELINES FOR RECIPIENTS OF NIH RESEARCH GRANTS AND CONTRACTS ON OBTAINING AND DISSEMINATING BIOMEDICAL RESEARCH RESOURCES, published on December 23, 1999 in the Federal Register) http://www.ott.nih.gov/policy/rt_guide_final.html. Accordingly, to address the interests of the research community and government in promoting the science of the genetic basis of drug addiction vulnerability, NIDA expects applicants who respond to this PA to develop and propose detailed plans for sharing the data and materials generated through the grant. It is expected that the Data Sharing Plan will specify the following elements: 1) creation of comprehensive and verified databases that contain all clinical, diagnostic, pedigree structure, and genotypic information collected and produced by the grant, 2) establishment of cell lines (from which DNA will be extracted and stored) from all protocol subjects from whom blood samples have been obtained, 3) a mechanism or protocol by which all databases and biological materials (DNA samples, cell lines) can be widely searched or distributed to qualified investigators in the scientific community, 4) a timetable specifying when various elements of the database (e.g., diagnostic, assessment, or genetic data) will be available for distribution. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale or justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register on March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, and is available on the web at the following URL address http://grants.nih.gov/grants/guide/notice-files/not94-100.html. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: It is the policy of NIH 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning these policies. NATIONAL ADVISORY COUNCIL ON DRUG ABUSE RECOMMENDED GUIDELINES FOR THE ADMINISTRATION OF DRUGS TO HUMAN SUBJECTS The National Advisory Council on Drug Abuse recognizes the importance of research involving the administration of drugs to human subjects and has developed guidelines relevant to such research. Potential applicants are encouraged to obtain and review these recommendations of Council before submitting an application that will administer compounds to human subjects. The guidelines are available on NIDA’s Home Page at www.nida.nih.gov under Funding or may be obtained by calling (301) 443-2755. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and the Institute or Center who agreed to accept assignment of the application. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. SPECIFIC INSTRUCTIONS FOR MODULAR GRANTS APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested, as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers, and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 FACE PAGE - Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages). At the top of the page, enter the total Direct Costs requested for each year. This is not a Form page. Under Personnel, list key project personnel, including their names, percent of effort, and role in the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (Direct plus F&A) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role in the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested Modular Direct Cost amount. Include the letter of intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the Form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, and - List selected peer-reviewed publications, with full citations. CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. The title and number of the PA must be typed on line 2 of the face page of the application form and YES box must be marked. 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) REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group and convened in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by an appropriate national advisory council or board. 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. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that 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. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities, and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Awards will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Jonathan D. Pollock, Ph.D. Division of Basic Research National Institute on Drug Abuse 6001 Executive Blvd., Room 4274, MSC 9555 Bethesda, MD 20892-9555 Telephone: (301) 443-6300 FAX: (301) 594-6043 Email: jp183r@nih.gov Direct inquiries regarding fiscal matters to: Gary Fleming, J.D., M.A. Grants Management Branch National Institute on Drug Abuse 6001 Executive Boulevard, Room 3131, MSC 9541 Bethesda, MD 20892-9541 Telephone: (301) 443-6710 FAX: (301) 594-6847 Email: gf6s@nih.gov Direct inquiries regarding review matters to: Teresa Levitin, Ph.D. Office of Extramural Affairs National Institute on Drug Abuse 6001 Executive Boulevard, Room 3158, MSC 9547 Bethesda, MD 20892-9547 Telephone: (301) 443-2755 FAX: (301) 443-0538 Email: tl25u@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.279. Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-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, and 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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