RFA-HD-02-009: FRAGILE X RESEARCH CENTERS

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FRAGILE X RESEARCH CENTERS Release Date: January 3, 2002 RFA: RFA-HD-02-009 National Institute of Child Health and Human Development (http://www.nichd.nih.gov) Letter of Intent Receipt Date: June 23, 2002 Application Receipt Date: July 23, 2002 PURPOSE The National Institute of Child Health and Human Development (NICHD), through its Mental Retardation and Developmental Disabilities (MRDD) Branch, invites investigators to submit grant applications to establish Fragile X Research Centers, affiliated with an existing NICHD Mental Retardation and Developmental Disabilities Research Center (MRDDRC), to conduct research to improve the diagnosis and treatment of, and to find a cure for, Fragile X syndrome. This initiative was developed primarily in response to the Children"s Health Act of 2000 (H. R. 4365) Section 452E, which directs that the " Director of the Institute, after consultation with the advisory council for the Institute, shall expand, intensify and coordinate the activities of the Institute with respect to research on the disease known as fragile X. The Director shall, to the extent that amounts are appropriated provide for the establishment of at least three fragile X research centers only if the grant or contract has been recommended after technical and scientific peer review required by regulations under section 492 The Director of the Institute, with the assistance of centers established shall conduct and support basic and biomedical research into the detection and treatment of fragile X. The Director of the Institute shall, as appropriate, provide for the coordination of the activities of the centers assisted...including providing for the exchange of information among the centers. Each center shall use the facilities of one institution, or be formed from a consortium of cooperating institutions, meeting such requirements as may be prescribed by the Director of the Institute. Support may be provided for a center for a period not exceeding 5 years. Such period may be extended for one or more additional periods, each of which may not exceed 5 years, if the operations of such center have been reviewed by an appropriate technical and scientific peer review group established by the Director and if such group has recommended to the Director that such period be extended " Fragile X syndrome, one of the most common causes of mental retardation and neuropsychiatric disease in humans, occurs as a result of the production of "fragile sites" by trinucleotide repeat expansion of several genes located on the X chromosome. While several genes affected by the expansion have been identified, the prevalence, risk factors, and nature of the high allele repeats, as well as the mechanism and timing of repeat amplifications in various populations, need further study. Mechanisms by which the expression of these genes is dysregulated, e.g., by methylation and acetylation, also need further study. Proteins whose function is altered by interaction with the products of these genes need to be identified and the nature of the interaction further clarified. Further correlation of the degree of expansion and expression of clinical manifestations of the fragile X phenotype, particularly behavioral manifestations such as autism, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and anxiety disorders, is needed. Experimental systems in model organisms to enable the study of neurobiologic, neuroendocrinologic, and reproductive system alterations need to be developed and/or studied further at the organismal, cellular, and molecular level at various developmental stages. The purpose of this RFA is to establish Fragile X Research Centers affiliated with existing MRDDRCs to stimulate research designed to increase our knowledge base relevant to Fragile X syndrome in these and other research areas by encouraging applications that include, but need not be limited to, developmental neurobiology, pathophysiology, genetics, proteomics, epidemiology, structure-function correlations, and clinical, behavioral and biobehavioral studies directly relevant to Fragile X syndrome. These Fragile X Research Centers are intended to serve as a national resource. They should form networks that foster communication, innovation, and high-quality research in Fragile X syndrome. They also should provide a stimulating, multidisciplinary environment that attracts both established and promising new investigators. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain "Healthy People 2010" at http://www.health.gov/healthypeople. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private, that currently have an MRDDRC P30 grant. The application may include components of the Fragile X Research Center that are located at the existing MRDDRC and/or at affiliated domestic or foreign sites. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to participate in the application for a Fragile X Center. Scientific personnel and institutional resources capable of providing a strong research base in Fragile X must be available for an existing MRDDRC to meet the requirements of this RFA. A strong institutional commitment at each institution involved also must be demonstrated. The commitment may take the form of faculty appointments for investigators, purchase of research equipment, or assignment of research space to facilitate collaborative research and interdisciplinary interaction. Affiliation with and utilization of at least one Core within an existing MRDDRC is required for a Fragile X Research Center application to be responsive to this RFA. For further information regarding the application, contact the Program Staff listed under INQUIRIES. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) Center Core Grant (P30) award mechanism. Responsibility for the planning, direction, and execution of the proposed projects will be solely that of the applicant. The application is to be submitted as a P30 supplement by the Principal Investigator of the MRDDRC, in collaboration with the person designated to be the Director of the Fragile X Research Center, who also shall serve as the Associate Director of the MRDDRC for Fragile X Research. The Principal Investigator of the MRDDRC may also serve as the Director of the Fragile X Research Center. The supplement within a P30 Center is designed to encourage and support broadly based multidisciplinary research programs that have a well-defined central research focus or objective in Fragile X syndrome research. This supplement, the Fragile X Research Center, is based on a unique and new concept for the purposes of this RFA: a "Center within a Center." Because the concept is unusual, careful attention must be paid by applicants to the requirements contained in this RFA. Applications failing to adhere to these instructions will be returned to the applicant without review. An important feature of this new "Center within a Center" concept is that the interrelationships among the individual projects and Cores proposed for the Fragile X Research Center will result in a greater contribution to the overall MRDDRC goals than if each project was pursued independently. The application requires a minimum of three related, integrated, and high-quality research projects that provide a multi-disciplinary, yet unified, approach to the problems being investigated by the Fragile X Research Center. The application may request support for certain common core resources, including core services provided by the existing MRDDRC. FUNDS AVAILABLE The NICHD intends to commit approximately $3.375 million in total costs [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund at least three Fragile X Research Centers as supplemental "Center within a Center" components of existing MRDDRC P30 Centers in response to this RFA. An applicant for a Fragile X Research Center grant may request a project period of up to five years and a budget for total costs of up to $1.125 million in the first year. However, NIH policy limits duration of competitive supplements to the time remaining on the parent grant, so formal budget requests in the application will have limitations. Prospective applicants should contact NICHD staff listed under INQUIRIES, below, for directions in preparing applications to deal with this situation. Although the financial plans of NICHD provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. RESEARCH OBJECTIVES Background Fragile X syndrome, one of the most common causes of inherited mental retardation and neuropsychiatric disease in human beings, affects as many as one in 2000 males and one in 4000 females. Trinucleotide repeat expansion of at least three genes located on the X chromosome has been associated with the formation of "fragile sites." Trinucleotide expansions within two of these genes, FRAXA (within the FMR1 gene) and FRAXE (within the FMR2 gene), are associated with mental retardation, while that at a third, FRAXF (not yet associated with a specific gene) is not. Mutations in the FMR1 gene, for example, produce expansion of CGG repeats in the 5" untranslated region of the gene and lead to a severely disabling neurodevelopmental disorder. Such expansion leads to physical, neurocognitive, and emotional characteristics linked to, but not exclusively determined by, alterations in the FMR1 gene or the level of its protein, FMRP. While such expansions can be detected in all races and ethnic groups, epidemiological studies to assess prevalence, risk factors, and the nature of the high allele repeats are needed, populations may not be equivalent with respect to the degree or type of fragile X expansion. The mechanism and timing of repeat amplifications in various populations, similarly, are not known. Approximately 15-25 percent of individuals with Fragile X syndrome also are diagnosed with mild to moderate autism and autism spectrum disorders. FMRP expression and autistic status appear to be associated with developmental outcome. Other clinical abnormalities associated with Fragile X syndrome include attention deficit hyperactivity disorder (ADHD) and anxiety disorders. Current methods for prenatal diagnosis of gene expansion of FRAXA, associated with FMR1 and its encoded protein, FMRP, are accurate, sensitive, and relatively inexpensive. For such methods to be applied as general screening techniques, more knowledge about prevalence, risk factors, and nature of high repeat alleles needs to be obtained. Because populations may not be equivalent with respect to fragile X expansion, consideration of ethical issues related to variability of phenotype, the possibility of mislabeling, and the value of screening if there is no definitive therapy, is required. Although FMR1 is subject to X inactivation, abnormal methylation appears to contribute to the phenotype observed in mosaic patients. These individuals experience upregulation of the FMR1 gene. Further, expanded repeats appear to be abnormally methylated from the start, although the mechanism by which such abnormal methylation occurs remains unknown. Expanded FMR1 genes are also "silenced" through a process of deacetylation. Studies focusing on alteration of both of these processes are needed. FMRP is found in both nucleus and cytoplasm, where it binds with mRNAs associated with ribonucleoproteins (RNPs) specifically associated with polyribosomes. In neurons, FMRP-associated RNPs are located in the cell body, as well as in the dendrites, at the base of dendritic spines. Thus, FMRP may play a role in synaptic function and plasticity. Studies to determine the specific RNAs bound by FMRP, particularly those to which the expanded FMRP binds, are needed to identify how FMRP modulates translation of interacting messages, and whether the messages modulated differ in the cell body and dendrite. Individuals with Fragile X syndrome also exhibit neuroendocrinologic and reproductive disorders. Macroorchidism occurs in males with overt Fragile X syndrome. Premature ovarian failure occurs in females who do not have the number of CGG repeats to produce overt Fragile X syndrome, but have an expanded number of repeats with few or no apparent neurological symptoms (premutation carriers). Structural, neurochemical, and hormonal abnormalities, therefore, need to be put together with a specific pathophysiological or neurodevelopmental mechanism. Variation in the cognitive and behavioral phenotype of the Fragile X syndrome has been demonstrated in intellectual functioning, learning disability, executive function, attention, hyperactivity, depression, anxiety, and autistic behaviors. The explanation for this variation in phenotypic expression may depend on understanding the role of genetics and brain development in cognition and behavior. Therefore, further studies are needed correlating the clinical manifestations of the fragile X phenotype with the neurodevelopmental processes that underlie the Fragile X syndrome. This will lead, in turn, to a model of neurodevelopmental variation in specific cognitive and behavioral dysfunction. For treatment modalities to be instituted, suppression of expansion, restoration of expression, small molecule agents, and gene replacement need to be considered. Animal models are necessary for the evaluation of therapeutic strategies. For animal models to be effective, definition of the animal phenotype is only as good as the characterization of the human phenotype. The human phenotype includes deficits in executive function and social-behavioral problems. Sensitivity to internal and environmental stimuli, particularly sensory stimuli, needs to be determined. Research Scope This RFA is designed to create Fragile X Research Centers whose participating investigators would direct research efforts toward neurobiological, behavioral, biobehavioral, and epidemiological studies relevant to understanding the genetic and pathophysiologic basis of Fragile X syndrome, studies that may lead to the development of novel or adapted treatment strategies. Examples of the types of studies addressing Fragile X syndrome that may be proposed in response to this RFA include, but are not limited to, the following: o Development of methods to better refine the definition of the clinical phenotype of Fragile X syndrome, focusing on its characteristic component behavioral and cognitive features. o Environmental studies including the influence of culture and ethnicity as variables in developing a better understanding of the correlation between genotype-phenotype and patient outcome. o Neurodevelopmental and longitudinal studies to characterize the neuropathological progression and inherent variability in fragile X patients in order to develop specific hypotheses about the initial (primary) abnormality, and to address the degree to which phenotypic variation relates to postnatal brain development. o Histological, neurochemical, brain-imaging, and structure-function studies to define the molecular, cellular, and/or biochemical basis of this disorder and facilitate development of specific hypotheses about the basic abnormalities involved in Fragile X syndrome. o Studies examining the mechanism by which fragile X genetic status affects the development, function, and dysfunction of the nervous system, particularly with respect to cognition and behavior. o Studies applying imaging, electrophysiology, pharmacology, molecular biology, and behavioral science techniques to follow the developmental trajectories of different brain functions and their influence on developing cognitive and motor skills. Animal models are important resources for studying pathology and therapeutic strategies. Although some animal models have been created, there is still need for models for behavioral screening as well as therapeutic interventions that include suppression of expansions and restoration of expression. Specifically, topics that may be addressed include, but are not limited to: o Creation of conditional tissue-specific targeted knock-out animal models. o Development and use of animal models that have specific relevance to fragile X based on clear neurodevelopmental, pathophysiological, genetic, and/or functional homology. o Development and use of animal models to test existing medications and develop new psychopharmacologic medications that are safe and effective for fragile X patients. Research Projects Research proposed for inclusion in the Fragile X Research Center must represent new research projects. Projects relevant to Fragile X syndrome research that are currently supported by the R01, P01 or other funding mechanisms may not apply for "supplemental" funds that extend or modify their scope under this RFA. Projects that represent competing continuations of existing R01 and P01 project components, however, are eligible to be incorporated into a Fragile X Research Center application as "new" research projects, provided that they withdraw any overlapping applications currently funded or under review. The budgets of individual research projects may not exceed $250,000 in total costs per year. SPECIAL REQUIREMENTS Collaborative Arrangements Two or more institutions that can demonstrate a feasible plan for collaborative research may apply to form a Fragile X Research Center. One of these institutions must have an existing MRDDRC. Evidence of prior collaboration and/or a plan for proposed collaborations between the investigators and proposed access to at least one Core facility at the affiliated MRDDRC should be cited. An existing MRDDRC may submit only one Supplemental "Center within a Center" Fragile X Research Center application. Individual Directors of Fragile X Research Center Projects or Cores may affiliate with more than one MRDDRC for the purpose of establishing a Fragile X Research Center. However, Research Project Directors must apply for support of unique, distinct, and non-overlapping research projects at each MRDDRC/Fragile X Research Center with which they affiliate. Core Directors may provide Core services for more than one Fragile X Research Center. However, with the exception of the Administrative Core, these Core services must not duplicate MRDDRC Core services at the affiliated MRDDRC. The application must provide details of agreements regarding sub-contracting arrangements, coordination, and support of activities at and among participating institutions, and must demonstrate the potential effectiveness of such collaboration for the ongoing work of the Fragile X Research Center. Center Structure and Requirements All applications for a Fragile X Research Center must be submitted through and by one of the 14 existing NICHD MRDDRCs, as a request for a Supplement to the P30 Center Core grant for the purpose of creating a "Center within a Center," the Fragile X Research Center within the existing MRDDRC. A list of these MRDDRCs is available at http://www.nichd.nih.gov/RFA/HD-02-009/HD-02-009.htm and from the program contact identified under INQUIRIES, below. o The application may consist (a) entirely of research projects and cores within the home institution of the MRDDRC, or (b) partly of research projects and/or cores from an MRDDRC home institution and partly of projects and cores to be located at one or more domestic or foreign institutions that together form a collaborative affiliation with the MRDDRC for the purposes of forming a Fragile X Research Center. In the latter case, at least one core proposed for use by the Fragile X Research Center must be among the existing Cores of the MRDDRC. Applications must have IACUC approval for all projects or Cores that involve the use of vertebrate animals PRIOR to the date of submission of the application. o An application for a competitive supplement to an existing grant must be submitted by the Principal Investigator of the existing grant as the Principal Investigator of the supplement request. In order to offer maximum flexibility and scientific expertise in leadership of the Fragile X Research Center, an individual other than the Principal Investigator of the MRDDRC may be identified as the Director of the Fragile X Research Center of the MRDDRC. An institution other than the parent institution of the MRDDRC may employ this individual. In this instance, the Director of the Fragile X Research Center shall be listed as the Co-Principal Investigator for the supplement request, and shall also be designated as the Associate Director of the MRDDRC for Fragile X Research. o It is the intent of the NICHD that the Fragile X Research Center shall be an identifiable entity as a "Center within a Center" in the organizational structure of the MRDDRC. Applicants must indicate how they intend to meet this requirement. Applicants must present a plan that identifies clearly how the Fragile X Research Center will enhance the affiliated MRDDRC mission, increase its diversity, and meet existing requirements for Core access. Similarly, the MRDDRC must indicate how each component of the Fragile X Research Center will benefit from its affiliation with the MRDDRC. NICHD also expects that the Directors of the Fragile X Research Centers will attend the annual meetings of the MRDDRC Directors with NICHD staff. Required Application Components Applications for P30 supplements in response to this RFA must contain descriptions of three components: (1) An Administrative Core unit, directed by the Fragile X Research Center Director, (2) at least three independent Research Projects, directed by Research Project Leaders, and (3) Support Cores, as needed, directed by Support Core Leaders. These components are described below. For Fragile X Research Centers that extend beyond an existing MRDDRC, at least one of the Support Cores to be accessed by Fragile X Research Center investigators must be an existing Core at the MRDDRC with which the Fragile X Research Center has established an affiliation. Each application must include all components, however, one or more of the components may be located at collaborating domestic and/or foreign institutions or at the affiliated MRDDRC (see below). o Fragile X Research Center Director: The scientist who is designated by the applicant institution to direct the Fragile X Research Center. Both the Principal Investigator of the MRDDRC and the Fragile X Research Center Director will assume responsibility and accountability to the applicant institution and to the NICHD for the performance and proper conduct of the Fragile X Research Center in accordance with the requirements specified in this RFA. The Fragile X Research Center Director is responsible for the Administrative Core unit. o Administrative Core: A separately budgeted administrative unit that manages daily operations of the Fragile X Research Center. The Administrative Core unit, under the direction of the Fragile X Research Center Director, will coordinate all the operations of the Fragile X Research Center. The Administrative Core will ensure that the aims of the Research Projects are carried out by the Research Project Leaders and that Support Cores provide the necessary services to further the research aims. The Administrative Core may propose to provide salaries and support for a limited number of administrative and clerical personnel, such as the Fragile X Research Center Director, secretaries, and clerical support staff. Staff will use criteria defined under revised OMB Circular A-21 to determine whether direct charging for administrative and clerical staff will be allowed. The Administrative Core, particularly if it is located at an institution other than that of the affiliated MRDDRC, may propose administrative support services, including supplies, duplication, telephone, and maintenance contracts for equipment when not covered by institutional Facilities and Administrative charges or by the Administrative Core of the affiliated MRDDRC. Travel by the Director of the Fragile X Research Center to meetings of the MRDDRC Directors to discuss scientific advances in the Fragile X Research Center should be included in the application. Other costs that may be proposed by the Administrative Core of the Fragile X Research Center include costs related to dissemination of research results to the scientific community and lay public and costs of research-related seminars or meetings designed to promote interdisciplinary interaction, education, or center cohesiveness. Costs may NOT be requested for salary and support of central administrative personnel usually paid from institutional Facilities and Administrative (overhead) charges, such as budget officers, grant assistants, and building maintenance personnel, for administrative activities such as public relations, health or educational services unrelated to the research, and travel of investigators, other than the Fragile X Research Center Director, to scientific meetings. o Research Projects: At least three independent research projects, each under a Research Project Leader, must be proposed. Projects proposed for support in the Fragile X Research Center should provide evidence of integrated synergy reminiscent of that expected in more traditional program project (P01) grant mechanism applications. Funds requested for individual research projects to be supported by the Cores of the Fragile X Research Center should conform to PHS 398 R01 instructions and requirements (http://grants.nih.gov/grants/funding/phs398/phs398.html). For each research project, a budget for total costs of up to $250,000 per year may be requested. However, for the purpose of this RFA, the budget should NOT be presented in modular grant format. Support for the research projects proposed for the Fragile X Research Center may be requested for a period of up to five years. However, funds for years beyond the duration of the applicant P30 MRDDRC will be contingent upon continued funding of the affiliated MRDDRC. o Research Project Leader: The individual responsible for directing one or more of the Research Projects of the Fragile X Research Center. The Research Project Leader may or may not be the Fragile X Research Center Director. o Support Core(s): At least one separately budgeted component(s) that provide(s) support for the research programs must be proposed. For the purposes of this RFA, use of core facilities located at other institutions is allowed and use of at least one Core at an existing, affiliated MRDDRC is required. Applicants for the Fragile X Research Center must provide evidence of accomplishment and progress to date of the Core unit(s) in the existing MRDDRC, and anticipated accomplishments and progress that will be made by projects proposed for the Fragile X Research Center. Except for the Administrative Core, the Fragile X Research Center Cores may not duplicate the particular services of existing Cores of the affiliated MRDDRC. Examples of Cores at existing MRDDRCs that investigators at the Fragile X Research Center might propose to access include, but are not limited to: Genetics or Molecular Genetics Core, Behavioral Science Core, Information Technology Core, Design and Statistical Computing Core, Human Subjects Core, Data Management and Analysis Core, Participant Services Core, Quantitative and Observational Methodology Core, Genomics Core, Transgenic Mouse Core, Database and Biostatistics Core, and/or Longitudinal Studies and Statistical Modeling Core. Applicants are encouraged to contact NICHD Program Staff prior to submission of the application to determine whether the Core services proposed for the Fragile X Research Center may represent duplication of Core services available at the proposed or affiliated MRDDRC. For the purposes of this RFA, each Core must provide essential facilities and services to at least TWO component projects of the Fragile X Research Center at all times during the period of award. This is an exception to the NICHD P30 Guidelines stating that each core should be utilized by three or more component projects. If only one of the component projects requires proposed Core support, then the required expertise, technology, and/or infrastructure should be integrated into the relevant component project and the Core eliminated as a separate entity. The application should provide: (1) a plan for implementation of satisfactory quality-control systems for services and facilities for each new core proposed, (2) documentation of quality-control systems already in place for Cores being accessed at the MRRDRC, (3) evidence of cost-effectiveness through mechanisms such as fee-for-service, in-kind, or other means. Centralization should lower the costs that would be incurred if the individual research projects proposed had to provide the same facilities and services, and (4) evidence that the proposed cores will increase the quality and productivity of the research projects receiving core support. Budgets for Core units may include salaries for support core staff, supplies (including animals), scientific equipment, computer facilities and services, travel of technical and administrative staff for technical training that would enhance the quality of core unit operation or travel required to maintain the operation of the core unit, minor renovation of alteration of existing facilities, and consultation services. o Support Core Leader(s): The individual responsible for directing a support Core facility. There may be one or more support Cores. These Cores would provide services to achieve the research goals. At least one of these individuals must be the Core Director of an existing and affiliated MRDDRC. Annual Meetings Due to the anticipated proprietary nature of the products under development, each Fragile X Research Center will act independently of the other. The Fragile X Research Center Director should attend the annual meetings of the Directors of the MRDDRCs with NICHD staff. Applications should include a request for funds to support attendance of the Fragile X Research Center Director at the annual meetings, as well as a statement of agreement to participate in these meetings. PRE-APPLICATION WORKSHOP An informational pre-application workshop addressing the scientific and administrative issues associated with this initiative will be held in April 2002 in Bethesda, Maryland. The purpose of the workshop is to (1) familiarize the potential applicant with established NIH guidelines and criteria for review, (2) discuss the areas of NICHD programmatic emphasis, and (3) facilitate the submission of a well-organized application. Logistics information, including date, time and location, will be posted on the NICHD home page (http://www.nichd.nih.gov/RFA/HD-02-009/HD-02-009.htm) and may be obtained from program staff listed under INQUIRIES, below. 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 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 AMENDMENT "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 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/or 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 Inclusion of Children as Participants in Research Involving Human Subjects," published in the NIH Guide for Grants and Contracts, March 6, 1998, and available at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff under INQUIRIES. Program staff also may provide additional relevant information concerning these policies. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. 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. This policy announcement is found 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. 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 RFA 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. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the names, addresses, telephone numbers, and institutions of the applicant, the Principal Investigator, i.e., the Director of the affiliated MRDDRC, and of the proposed Director of the Fragile X Research Center, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although the letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information it contains allows NICHD staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Mary Lou Oster-Granite by June 23, 2002 at the address listed under INQUIRIES, below. APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants. This version of the PHS 398 is available in an interactive, searchable format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov. Application Instructions Because the PHS 398 (rev. 5/2001) is designed primarily for the traditional R01 application, applicants will need to modify and expand several sections outlined in the PHS 398 instructions to provide the additional information required for a P30 Supplement application responsive to this RFA. To ensure that the essential information is provided in a systematic fashion, all applications should be submitted in a format such as that outlined in Appendix I of the P30 guidelines. Because the P30 supplement application requests funds for direct research support, each project must be presented in as much detail as if it were a request for an R01, within PHS 398 page limitations. Applications submitted in response to this RFA should be prepared in accordance with the instructions presented in this RFA. Information on the suggested format of applications may be found at http://www.nichd.nih.gov/funding/mechanism/p30_guide.cfm. Submission Instructions The RFA label available in the PHS 398 (rev. 5/01) application form must be stapled to the bottom of the face page of the application and must display the RFA number HD-02-009. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note that this is in pdf format. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three 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) Applications delivered by individuals to the Center for Scientific Review will no longer be accepted. At the time of submission, two additional copies of the application and five sets of all appendices should be sent to: Robert Stretch, Ph.D. Acting Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Blvd., Room 5E03, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by July 23, 2002. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA 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 substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and for responsiveness to this RFA by NICHD staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD in accordance with the review criteria stated below. NO site visits will be made in the review of these applications, all information required for evaluation must be contained in the application. As part of the initial merit review, all applications will receive a written critique and may 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 the National Advisory Child Health and Human Development Council. Review Criteria Peer review of the scientific and technical merit of these P30 supplement, Fragile X Research Center applications will focus on three areas: (1) review of the individual component projects, 2) review of the individual cores, and (3) review of the program as an integrated effort and the overall merit of the program. The criteria listed in the NICHD P30 Guidelines, Appendix III, P30 Review Criteria, available at: http://www.nichd.nih.gov/funding/mechanism/p30_guide.cfm, will be considered by reviewers in evaluating the proposed projects, cores, and the program as an integrated effort, as well as the overall merit of the program for all applications responding to this RFA. With respect to these criteria and for the purposes of this RFA, "center" investigators and services refer to those individuals and services associated specifically with the proposed Fragile X Research Center, not necessarily with the MRDDRC P30 Center as a whole. In addition, reviewers will evaluate: o institutional commitment at each site, when more than one institution is involved, o the presence of administrative and organizational structure conductive to attaining the objectives of the "Center within a Center," the Fragile X Research Center, o the leadership ability and scientific stature of both the Principal Investigator, who is the Director of the MRDDRC, and the Co-Investigator, who is the proposed Director of the Fragile X Research Center, their abilities to meet their respective program"s demands of time and effort, and their ability to promote the mission of both the Fragile X Research Center and the affiliated MRDDRC. Schedule Letter of Intent Receipt Date: June 23, 2002 Application Receipt Date: July 23, 2002 Peer Review Date: October/November 2002 Council Review: January 2003 Earliest Anticipated Start Date: April 2003 AWARD CRITERIA Criteria that will be used to make award decisions include scientific and technical merit as determined by peer review, programmatic priorities and relevance, program balance, and the availability of funds. INQUIRIES Potential applicants are strongly encouraged to contact program staff early in application development with any questions regarding the responsiveness of their proposal to the goals of this RFA. Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Mary Lou Oster-Granite, Ph. D. Mental Retardation and Developmental Disabilities Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B-09, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1383 FAX: (301) 496-3791 E-mail: mo96o@nih.gov Direct inquiries regarding fiscal matters to: Ms. Mary E. Daley Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A-17, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1305 FAX: (301) 402-0915 E-mail: md74u@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865. 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 inter-governmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant 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, 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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