RELEASE DATE:  April 10, 2002

PA NUMBER:  PAR-02-097

EXPIRATION DATE:  April 1, 2005, unless reissued

National Institute on Aging (NIA)
National Heart, Lung and Blood Institute (NHLBI)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Child Health and Human Development (NICHD)


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


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.


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 
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 

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: 

Martin GM, Oshima J. 2000.  Lessons from human progeroid syndromes.  Nature 


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, and from The 
Progeria Research Foundation (  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.


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


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


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.


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 

o  Direct your questions about scientific/research issues to either of the 

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

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

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

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

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

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


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/01) available at in an interactive 
format.  For further assistance contact Grantsinfo, Telephone 301/710-0267, 
Email  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  Application 
deadlines are also indicated in the PHS 398 application kit.

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 includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

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  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  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 


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 
( 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


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 

(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 

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.


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


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.

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

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

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 

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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