and Human Services (HHS)
EXPIRED
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: [email protected]
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: [email protected]
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: [email protected]
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: [email protected]
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 [email protected].
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.
Weekly TOC for this Announcement
NIH Funding Opportunities and Notices
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