INNOVATION GRANTS FOR RESEARCH ON HUTCHINSON-GILFORD PROGERIA SYNDROME RELEASE DATE: April 10, 2002 PA NUMBER: PAR-02-097 EXPIRATION DATE: April 1, 2005, unless reissued National Institute on Aging (NIA) (http://www.nia.nih.gov/) National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/index.htm) National Institute of Dental and Craniofacial Research (NIDCR) (http://www.nidr.nih.gov/) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Research Resources o Mechanism of Support 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 This Program Announcement (PA) is a new initiative to support research on the mechanistic basis of Hutchinson-Gilford progeria syndrome (HGPS). This syndrome has some features typical of normal human aging, and is thus often referred to as a premature aging syndrome. This incurable, terminal syndrome is characterized by short stature, abnormal skeletal and tooth development, scleroderma-like skin changes, and cardiovascular disease. Children usually die of heart attacks or strokes at an average age of 13 years. Very little research has been done on this syndrome because it is extremely rare (about 1 in 10 million births), and there has been limited access to the patient population. Better understanding of the causes of this syndrome could lead to better insights into mechanisms of both development and aging. RESEARCH OBJECTIVES The mode of inheritance, molecular basis and pathomechanisms of HGPS are undefined. Although HGPS mimics some aspects of normal aging such as loss of hair, loss of subcutaneous adipose tissue and death due to cardiovascular disease, a more critical examination of the literature suggests that some of the pathologies associated with HGPS are indicative of developmental abnormalities and extracellular matrix defects. HGPS patients appear normal at birth, and the disease is usually diagnosed near the end of the second year of life after failure-to-thrive commences, suggesting that fetal, but not post-natal, development is normal. HGPS patients do not exhibit typical osteoporosis or osteoarthritis, but rather skeletal dysplasia. HGPS is characterized by delayed closure of the fontanelles, progressive resorption of the distal clavicles and phalanges, slowed vertebral development, thin long bones, and delayed tooth eruption. Scleroderma-like cutaneous changes such as uneven thickening and tightening of the skin, and dermal fibrosis may reflect extracellular matrix defects. The nature of the cardiovascular disease is poorly understood, and it is not known whether the vascular plaques and cardiac fibrosis are similar to those associated with typical atherosclerosis of aging. Intellectual and neurological development remains entirely normal. Through this PA the National Institute on Aging of the National Institutes of Health, in collaboration with the other Institutes listed above, seeks to encourage research projects that will take a fresh approach to understanding the molecular basis of HGPS. Another purpose of the PA is to interest new investigators in research on HGPS. Examples of research topics appropriate for the Program Announcement include, but are not limited to, proposals to: o identify and characterize the genetic locus responsible for HGPS, and determine whether HGPS is caused by a spontaneous autosomal dominant mutation arising in the germline. o generate a mouse model with the HGPS phenotype. o elucidate the possible role, if any, of extracellular matrix metabolism in HGPS. o determine the nature of the vascular occlusion leading to premature myocardial infarctions and strokes. o elucidate the molecular basis for the short stature and the abnormal development of various skeletal and craniofacial structures that occur in HGPS patients, including delayed tooth eruption. o determine which aspects of HGPS, if any, are due to deficiencies in basic processes such as signal transduction, stem cell proliferation and function, cellular damage and repair mechanisms, cell replication, apoptosis, etc. o determine and validate the differences in gene expression between normal and HGPS fibroblasts and/or other tissue types. o establish a registry of clinical data and bank of research resources. Applicants may wish to consult one or more of the following reference articles: DeBusk FL. The Hutchinson-Gilford Progeria Syndrome. 1972. J. Pediatrics 80: 697-794. Clark MA, Weiss AS. 1993. Elevated levels of glycoprotein gp200 in progeria fibroblasts. Mol. Cell Biochem. 120: 51-60. Ly DH, et al., 2000. Mitotic misregulation and human aging. Science 287: 2486-2492. Martin GM, Oshima J. 2000. Lessons from human progeroid syndromes. Nature 408:263-266. RESEARCH RESOURCES Fibroblast and lymphoblastoid cell lines from HGPS patients are available from the Coriell Institute for Medical Research (CIMR). Information about these cell lines is available at http://locus.umdnj.edu/nia, and from The Progeria Research Foundation (www.progeriaresearch.org). CIMR supplies 10 typical HGPS fibroblast cell lines from 10 different families. Of these 10 cell lines, 7 are from male patients and 3 are from female patients. Three of these lines have parental fibroblasts available. Information about race is available for some lines. DNA from one HGPS fibroblast cell line is available. Three typical HGPS cell lines that are not held at CIMR are available through The Progeria Research Foundation. CIMR also provides 6 HGPS lymphoblastoid cell lines (4 male and 2 female), along with their DNA. Three of these lymphoblaotoid cell lines have corresponding fibroblast lines available. In addition, 2 of these HGPS lines have familial lymphoblastoid lines available. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant R21 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. You may request up to two years of support and up to $100,000 per annum in direct costs. Contact the program staff listed under INQUIRIES for further information. This award is non-renewable because it is hoped that successful grantees funded through this exploratory phase program will elect to seek continuing support for research further along the development pipeline through the RO1 or PO1 grant mechanisms. This PA uses just-in-time concepts. It also uses the modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). 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, whether a new or established investigator, 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 by the following mechanism. Women, individuals from underrepresented racial and ethnic groups, as well as individuals with disabilities are encouraged to apply as principal investigators. 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 three areas: scientific/research, peer review, and financial or grants management issues. o Direct your questions about scientific/research issues to either of the following: Dr. Huber R. Warner Biology of Aging Program National Institute on Aging Gateway Building, Room 2C231 Bethesda, MD 20892- 9205 Telephone: (301) 496-4996 FAX: (301) 402-0010 Email: warnerh@nia.nih.gov Dr. Stephen Goldman Vascular Biology Research Program Division of Heart and Vascular Disease National Heart, Lung and Blood Institute 6701 Rockledge Drive, Suite 10193, MSC 7956 Bethesda, MD 20892 7956 Carrier Zip 20814 Telephone: (301) 435-0565 FAX: (301) 480-2858 Email: goldmans@nhlbi.nih.gov Dr. Rochelle Small, Director Developmental Biology and Mammalian Genetic Program National Institute of Dental and Craniofacial Research Building 45, Room 4AN-18D Bethesda, MD 20892-6402 Telephone: (301) 594-9898 FAX: (301) 480-8318 Email: rochelle.small@nih.gov Dr. A. Tyl Hewitt Developmental Biology, Genetics and Teratology Branch National Institute of Child Health and Human Development Building 6100, Room 4B01 9000 Rockville Pike, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5541 FAX: (301) 480-0303 Email: th119v@nih.gov o Direct your questions about peer review issues to: Dr. Mary Nekola Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue Suite 2C212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 FAX: (301) 402-0066 Email: Nekolam@nia.nih.gov o Direct inquiries regarding financial or grants management matters to: Linda Whipp Grants and Contracts Management Office National Institute on Aging Gateway Building, Room 2N212 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: whippl@nia.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/01) available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact Grantsinfo, Telephone 301/710-0267, Email Grantsinfo@nih.gov. The R21 application will be limited to a maximum of 15 pages for the following parts: Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods. 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: 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. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to: Center for Scientific Review National Institute of Health 6701 Rockledge Drive, Room 1040, MSC 771 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) In addition, to prepare for review of the application, submit two additional exact photocopies of the application directly to: Dr. Mary Nekola Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212, MSC 9205 Bethesda, MD 20892-9205 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. APPLICATION PROCESSING: Applications must be received by or 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. 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 May 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 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 your 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 Investigation o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific input, and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative, but is essential to move a field forward. Note that the R21 grant mechanism does not require extensive Preliminary Data. (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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator, and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: 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. INCLUSION: By necessity all research samples will have been derived from children. There are very few individuals living with this syndrome. Reviewers will take these limiting facts into account in assessing the adequacy of plans to include subjects from both genders, all social and ethnic groups (and subgroups) and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Required Federal Citations below.) DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and required period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to this PA will compete for available funds with all other 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 INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH INVOLVING HUMAN SUBJECTS: It is the policy of the NIH that females and members of minority groups must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided. Investigators responding to this PA are encouraged to use diverse samples in their research as far as possible given the limited availability of samples. By necessity, all research samples will have been derived from children. In the near future it is anticipated that some tissue samples will be available through the Progeria Research Foundation, but few applicants will have direct access to HGPS patients as there are only about 10 living cases of HGPS currently known in the United States. 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. 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. URLS IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. 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 side. 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 on Innovation Grants for Research on Hutchinson-Gilford Progeria Syndrome 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 Catalogue of Federal Domestic Assistance No. 93.866, 93.837, 93.121, and 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 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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