EXPLORATORY GRANTS FOR GENOMIC IMPRINTING AND ENVIRONMENTAL DISEASE SUSCEPTIBILITY

Release Date:  December 22, 1999

PA NUMBER:  PA-00-034

National Institute of Environmental Health Sciences

THIS PROGRAM ANNOUNCEMENT (PA) USES THE "MODULAR GRANT" AND "JUST-IN-TIME" 
CONCEPTS.  THE PA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION 
INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO 
THIS PA.

PURPOSE

The National Institute of Environmental Health Sciences (NIEHS) invites 
research grant applications from interested investigators to conduct timely, 
innovative, and mechanistic research on the importance of genomic imprinting 
in determining susceptibility to environmentally induced diseases through a 
program of exploratory investigator-initiated R21 grants.

The exploratory/developmental (R21) grant mechanism is used for pilot 
projects or feasibility studies to support creative, novel, high risk/high 
payoff research that may produce innovative advances in science.  This PA is 
to encourage applications from individuals who are interested in testing 
novel or conceptually creative ideas to understand the potential role 
environmental agents play in causing epigenetic changes in the DNA that can 
alter imprint gene expression, thereby resulting in a multitude of genetic 
diseases including cancer and neuro-behavioral disorders.

This PA will expire 3 years from the first receipt date.  That is, the final 
receipt date will be October 1, 2002.  The NIH Grants policy statement apply 
to these awards.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2000," a PHS-
led national activity for setting priority areas.  This PA, EXPLORATORY 
GRANTS FOR GENOMIC IMPRINTING AND ENVIRONMENTAL DISEASE SUSCEPTIBILITY, is 
related to the priority area of environmental health.  Potential applicants 
may obtain a copy of "Healthy People 2000" (Full Report:  Stock No. 017-001-
00474-0 or Summary Report:  Stock No. 017-001-00473-1) through the 
Superintendent of Documents, Government Printing Office, Washington, DC 
20402-9325 (telephone 202-512-1800), or at 
http://odphp.osophs.dhhs.gov/pubs/hp2000
 
ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit 
organizations, public and private, such as universities, colleges, hospitals, 
laboratories, units of State and local governments, and eligible agencies of 
the Federal Government.  Applications may be from a single institution or may 
include arrangements with one or more institutions (e.g., consortia, if 
appropriate).  Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health 
(NIH) exploratory/developmental grant (R21) mechanism.  Applicants will be 
responsible for the planning, direction, and execution of the proposed 
project.  All PHS and NIH grants policies will apply to applications received 
and awards made in response to this PA.  Applicants may request up to 
$100,000 per year in direct costs.  The total project period for an 
application submitted in response to this PA may not exceed 2 years.  These 
grants are non-renewable and continuation of projects developed under this 
program will be through the traditional unsolicited investigator initiated 
grant program.  Amended applications will be accepted.

Though the size of the award may vary with the scope of research proposed, it 
is expected that applications will stay within the budgetary guidelines for 
an exploratory/ developmental project.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grant 
applications can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm 

Applications will request direct costs in $25,000 modules.  A feature of the 
modular grant is that no escalation is provided for future years, and all 
anticipated expenses for all years of the project must be included within the 
number of modules being requested. Only limited budget information is 
required and any budget adjustments made by the Initial Review Group will be 
in modules of $25,000.

RESEARCH OBJECTIVES

Background

The NIEHS supports basic research and prevention/intervention studies related 
to environmental health through research project grants.  Historically, this 
research has emphasized evaluation of health risks or disease outcomes, 
rather than the fundamental mechanisms of disease etiology.  However, with 
the exception of Small Research Grants (R03), primarily targeted to new or 
previously unfunded areas of investigations, it has been difficult for 
scientists to obtain funding for hypothesis development, methods development, 
new intervention approaches, or feasibility studies.  It is expected that 
these R21 grants will serve as a basis for planning future mechanistic 
research project grant applications (R01).  This PA, therefore, is intended 
to stimulate innovative approaches to further enhance genomic imprinting 
research, and specifically, to better understand the role of the environment 
in its modulation.

Because the exploratory grant mechanism is designed to support innovative 
ideas, preliminary data as evidence of feasibility are NOT required.  
However, the applicant does have the responsibility for developing a sound 
research plan with a strong theoretical or empirical basis. Originality of 
the approach and potential significance of the proposed research are major 
considerations in the evaluation.

Research Goals and Scope

Although two copies of autosomal genes are present in everybody, in some 
instances only one copy is expressed.  Surprisingly, it was found that the 
expressed copy was dictated by whether that particular allele was inherited 
from the father or the mother, a phenomenon termed imprinting.

Genomic imprinting in humans is a recently recognized phenomenon, but it has 
already been demonstrated to have a role in several developmental and 
pathological processes.  There are now more than 25 identified imprinted 
genes, and estimates based on mouse models indicate that as many as 100 to 
200 may exist.  We do not yet have a clear understanding of their function in 
normal development, though it appears that some imprinted genes are involved 
in fetal and placental growth, cell proliferation, and adult behavior.  
Imprinting and X chromosome-inactivation, both assure that normally only one 
of the two identical gene sequences will be expressed in the cell.  
Genomic imprinting is not a cause of human disease itself, but rather is a 
normal process which, when disrupted, causes human disease.  The origin of 
chromosomal deletions and nondisjunction, which cause such imprinting 
disruptions (much as they cause other human disorders when they affect 
non-imprinted genes), is unknown despite many years of research.  Efforts are 
now focused on identification of intrinsic structural characteristics of the 
DNA at the breakpoint sites, since this may provide insight into the origin 
of chromosomal deletions, especially those that seem to recur with some 
frequency, such as in Prader-Willi and Angelman syndromes.  For example, 
recently, a 50-60 KB complex repeat has been found to occur in the vicinity 
of the common PWS/AS breakpoints, but not elsewhere in the genome, suggesting 
that this structure may predispose to homologous recombination.  Earlier 
studies identified an increased likelihood of occupational hydrocarbon 
exposure among fathers giving birth to children with Prader-Willi syndrome 
when compared with published general population figures, suggesting that this 
may be a factor predisposing to chromosomal deletion in PWS.  Indeed 
environmental factors predisposing to chromosomal breakage at structural 
predisposed sites remain a fertile ground for future research efforts.

Further search for imprinted genes, as well as for candidate genes associated 
with specific defects of genomic imprinting, are likely to lead to insights 
into the reason that this mechanism of control of gene expression arose.  It 
will also provide insight into the pathogenesis of disorders resulting from 
abnormalities in imprinting.

Genomic imprinting modulates gene expression by providing the means to turn 
specific alleles of a gene on or off in a parent-of-origin dependent manner.  
The imprint silences the allele from one parent.  However, parental 
imprinting is not an all-or-none phenomenon.  It is by design an inherently 
unstable mechanism of gene regulation.  Both genetic and environmental 
factors can affect the imprinting process and alter the level of expression 
of imprinting genes.  In addition to developmental and tissue-specific 
variation, imprinting can also be polymorphic among individuals. 

DNA methylation and chromosome structure regulate genomic imprinting.  Thus, 
environmental factors capable of causing epigenetic changes in the DNA can 
potentially alter imprint gene expression and result in genetic diseases that 
include cancer and behavioral disorders.

Some of the questions that need to be answered include:

1.  Can environmental agents alter gene expression by altering chromatin 
structure?

2.  How permanent are these changes?

3.  Can environmental agents alter the imprinting status of the genome?

4.  Can environmental agents alter the developmental program of imprinting?

5.  If environmental agents induce changes in imprinting patterns, are these 
associated with human diseases or disorders?

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 subpopulations must be included in all NIH supported biomedical and 
behavioral research projects involving human subjects unless a clear and 
compelling rationale and justification is provided 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 research involving human subjects should read the 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research," which have been published in the Federal Register of March 28, 
1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, 
Volume 23, Number 11, March 18, 1994 available on the web at the following 
URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html

Investigators also may obtain copies of the policy from the program staff 
listed under INQUIRIES. Program staff may also provide additional relevant 
information concerning policy.

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 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 the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 
address: http://grants.nih.gov/grants/funding/children/children.htm 

APPLICATION PROCEDURES

The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets.  Only 
limited budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only when there 
is a possibility for an award.  It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and Institute 
staff.  The research grant application PHS 398 Form (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

Application kits are available at most institutional offices of sponsored 
research and may be obtained from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge Drive, 
MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
grantsinfo@nih.gov. For those applicants with internet access, the 398 kit 
may be found at http://grants.nih.gov/grants/funding/phs398/forms_toc.html 

Applicants are strongly encouraged to contact the program staff listed under 
INQUIRIES with any questions regarding their proposed project and the goals 
of this PA.

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up 
to a total direct cost request of $100,000 per year.  The total direct costs 
must be requested in accordance with the program guidelines and the 
modifications made to the standard PHS 398 application instructions described 
below:

PHS 398

o  FACE PAGE - Items 7a and 7b should be completed, to indicate Modular 
Direct Costs (in $25,000 increments) and Total Costs [Modular Direct plus 
Facilities and Administrative (F&A) costs] for the initial budget period.  
Items 8a and 8b should be completed indicating the Direct and Total Costs for 
the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete page 4 of 
the PHS 398 Form (rev 4/98).  It is not required and will not be accepted 
with the application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the 
categorical budget table on page 5 of the PHS 398 Form.  It is not required 
and will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page.  (For sample pages, see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  At the top of the 
page, enter the total direct costs requested for each year.  This is not a 
form page.

o  Under Personnel, list key project personnel, including their names, 
percent of effort, and roles on the project.  No individual salary 
information should be provided.  However, the applicant should use the NIH 
appropriation language salary cap and the NIH policy for graduate student 
compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct 
plus facilities and administrative) for each year, each rounded to the 
nearest $1,000. List the individuals or organizations with whom consortium or 
contractual arrangements have been made, the percent effort of key personnel, 
and the role on the project.  Indicate whether the collaborating institution 
is domestic or foreign.  The total cost for a consortium/contractual 
arrangement is included in the overall requested modular direct cost amount. 
Include the Letter of Intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the 
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a 
specific role in the proposed project, as well as to evaluate the overall 
qualifications of the research team.  A biographical sketch is required for 
all key personnel, following the instructions below.  No more than three 
pages may be used for each person.  A sample biographical sketch may be 
viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last 3 years;
- List selected peer-reviewed publications, with full citations.

o  CHECKLIST - This page should be completed and submitted with the 
application.  If the F&A rate agreement has been established, indicate the 
type of agreement and the date.  It is important to identify all appropriate 
exclusions that were used in the calculation of the F&A costs for the initial 
budget period and all future budget years.

o  The applicant should provide the name and telephone number of the 
individual to contact concerning fiscal and administrative issues, if 
additional information is necessary, following the initial review.

APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED 
UNRESPONSIVE TO THIS PA AND WILL BE RETURNED WITHOUT FURTHER REVIEW.

The PA 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 five signed, exact, single-sided 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 will be accepted on the standard application receipt dates for 
investigator initiated research as indicated in the PHS 398 directions. The 
Center for Scientific Review (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 substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Applications 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 receive a written critique and undergo a process in which 
only those applications deemed to have the highest scientific merit, 
generally the top half of applications under review, will be discussed, 
assigned a priority score, and 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 human health. 
The reviewers will comment on the following aspects of the application in 
their written critiques in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals. Each 
of these criteria will be addressed and considered by the reviewers in 
assigning the overall score weighting them as appropriate for each 
application. Note that the application does not need to be strong in all 
categories to be judged likely to have a major scientific impact 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.

(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? Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3)  Innovation:  Does the project employ novel concepts, approaches or 
method?  Are the aims original and innovative? Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4)  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)?

(5)  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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research

o 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.

AWARD CRITERIA

Applications will compete for available funds with all other recommended 
applications.  The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priority

INQUIRIES

Inquiries concerning this PA are strongly encouraged. The opportunity to 
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding general programmatic issues to:

Jose M. Velazquez, Ph.D.
Scientific Program Administrator
Chemical Exposures and Molecular Biology Branch
Office of Program Development
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Post Office Box 12233 (EC-21)
Research Triangle Park, NC 27709
Telephone: (919) 541-4998
Fax: (919) 316-4606
E mail: velazqu1@niehs.nih.gov 

Direct inquiries regarding fiscal matters to:

Ms. Laura Williams-Boyd
Grants Management Specialist
Grants Management Branch (EC-22)
Office of Program Operations
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
Post Office Box 12233 
Research Triangle Park, NC  27709
Telephone: (919) 541-7629
Fax: (919) 541-2860
Email: Willia27@niehs.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.113.  Awards are made under authorization of the 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, 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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