THE BIOLOGICAL BASIS OF HUTCHINSON-GILFORD SYNDROME (HGS): RELATIONSHIP TO MUTATIONS IN THE LAMIN A/C GENE (LMNA) AND TO OTHER KNOWN LAMINOPATHIES RELEASE DATE: February 10, 2003 PA NUMBER: PA-03-069 EXPIRATION DATE: March 1, 2006 National Institute on Aging (NIA) (http://www.nia.nih.gov) National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov/index.htm) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.866 and 93.837 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 to understand how mutations in the gene for lamin A/C affect nuclear structure, thus leading to both dysfunction of the nuclear envelope, and depending on the mutation, Hutchinson-Gilford syndrome in humans (Eriksson et al., manuscript in preparation). Lamins A and C are coded by a single developmentally regulated gene designated LMNA; lamin C is a splice variant and lacks the carboxyl terminus present in lamin A. At least 6 other rare human disorders due to lamin A/C mutations (known collectively as laminopathies) besides HGS have been described so far: Emery Dreifuss muscular dystrophy (Bonne et al., 1999), dilated cardiomyopathy (Fatkin et al., 1999), familial partial lipodystrophy (Shackleton et al., 2000), limb girdle muscular dystrophy (Muchir et al., 2000), Charcot-Marie-Tooth disorder type 2 (De Sandre-Giovanni et al., 2002), and mandibuloacral dysplasia (Novelli et al., 2002). These disorders and their relationship to LMNA mutations have been reviewed recently {Burke and Stewart (2002)}, and Hutchinson (2002) has reviewed the function of lamins in the nuclear envelope. RESEARCH OBJECTIVES Lamin A is a major component of the nuclear envelope, so mutations in this gene are likely to have a broad impact on both nuclear structure and function. How aberrant nuclear structure and function lead to HGS and the other various disorders affecting such a variety of tissues is currently unknown. Through this PA the National Institute on Aging and the National Heart, Lung and Blood Institute seek to encourage mechanistic research projects that will shed light on the molecular basis of Hutchinson-Gilford syndrome and the other laminopathies arising from defects in LMNA. Clinical research proposals will not be considered to be responsive to this program announcement. Examples of research topics appropriate for this Program Announcement include, but are not limited to, proposals to: o Characterize changes in nuclear structure and/or post-translational processing of nuclear envelope proteins caused by mutations in the LMNA gene. o Determine how these changes in nuclear structure lead to nuclear and cellular dysfunction, with particular emphasis on effects on chromatin organization, gene expression, RNA processing, DNA replication and repair; vulnerability to apoptosis; anchorage of nuclear envelope proteins; and movement of macromolecules between the nucleus and cystoplasm. o Relate these changes to the specific pathologies observed in HGS and other laminopathies, e.g., differentiation of stem cells into adipocytes and muscle cells. o Develop interventions to reverse or attenuate cellular dysfunction due to lamin A mutations. o Generate and characterize appropriate transgenic mice for studying the various laminopathies with particular emphasis on how various LMNA mutations induce muscle dystrophy, bone dysplasia, lipodystrophy, and cardiac myopathy. o Elucidate why the HGS mutation recapitulates most of the pathologies of the other laminopathies, but has such a dramatic effect on longevity. o Characterize age-related changes in lamins and the nuclear envelope, and determine whether these play any role in development of adverse phenotypes during normal aging. o Determine the cell-specific functions of the lamins in cells of the cardiovascular system, such as endothelial cells and cardiac and vascular smooth muscle cells, and the molecular mechanisms through which these proteins control and regulate cellular function. o Determine how changes in the nuclear interactions of the lamins contribute to cardiovascular disease. Applicants may wish to consult the following review articles, or one of the references on specific laminopathies: Review articles Burke B, Stewart CL. 2002. Life at the edge: The nuclear envelope and human disease. Nature Reviews: Molecular Cell Biology 3: 575-585. Hutchinson CJ. 2002. Lamins: Building blocks or regulators of gene expression? Nature Reviews: Molecular Cell Biology 3: 848-858. Articles on specific laminopathies Bonne G, et al., 1999. Mutations in the gene coding lamin A/C cause autosomal dominant muscular dystrophy. Nature Genetics 21: 285-288. De Sandre-Giovanni A. et al., 2002. Homozygous defects in LMNA, encoding lamin A/C nuclear envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am. J. Hum. Genet. 70:726-736. Fatkin D, et al., 1999. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated myopathy and conduction system disease. N. Engl. J. Med. 341:1715-1724. Muchir A. et al., 2000. Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances. Hum. Mol. Genet. 9:1453-1459. Novelli G. et al., 2002. Mandibuloacural dysplasia is caused by a mutation in LMNA encoding lamin A/C. Am. J. Hum. Genet. 71:426-431. Shackleton. S. et al., 2000. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nature Genetics 24:153-156. Research resources Fibroblast and lymphoblastoid cell lines from HGS 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 (http://www.progeriaresearch.org). CIMR supplies 10 typical HGS 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 HGS fibroblast cell line is available. Three typical HGS cell lines that are not held at CIMR are available through The Progeria Research Foundation. CIMR also provides 6 HGS lymphoblastoid cell lines (4 male and 2 female), along with their DNA. Three of these lymphoblastoid cell lines have corresponding fibroblast lines available. In addition, 2 of these HGS lines have familial lymphoblastoid lines available. The NIGMS repository at CIMR contains 2 cell lines from a single limb girdle muscular dystrophy patient (a fibroblast and a lymphoblastoid cell line plus DNA) and 6 cell lines from one Charcot-Marie-Tooth family (fibroblasts from 5 affected and 1 non-affected family member). MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) research project grant R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. Contact the program staff listed under INQUIRIES for further information. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups, as well as individuals with disabilities, are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research, and financial or grants management issues. Direct your questions about scientific/research issues to either of the following: Dr. Felipe Sierra Biology of Aging Program National Institute on Aging Gateway Building, Room 2C231 Bethesda, MD 20892 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: sierraf@nia.nih.gov Dr. Stephen Goldman Vascular Biology Research Program Division of Heart and Vascular Disease National Heart, Lung and Blood Institute Bethesda, MD 20892-7956 Carrier Zip 20814 Telephone: (301) 435-0560 FAX: (301) 480-2858 Email: goldmans@nhlbi.nih.gov Direct questions 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 Owen Bobbitt Grants Operation Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Rockledge 2 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Tel: 301-435-0177 FAX: 301-480-0422 Email: bobbitto@nhlbi.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact Grantsinfo, Telephone (301) 710-0267, Email Grantsinfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of the NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award; and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review National Institute of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda 20817 (for express/courier service) APPLICATION PROCESSING: Applications must be received by or mailed before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA that is essentially the same as one currently pending initial review unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score. o Receive a second level review by the 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 the stated goals o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have major scientific input, and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative, but is essential to move a field forward. SIGNIFICANCE: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS 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 recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review. o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier (s) for the hESC line (s) to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protection 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. Furthermore, we caution reviewers 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 The Biological Basis of 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 Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant 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, 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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