NUTRIENT INFLUENCE ON GENE REGULATION AND EXPRESSION

NIH GUIDE, Volume 21, Number 17, May 8, 1992



PA NUMBER:  PA-92-77



P.T. 34



Keywords:

  Gene Regulation 

  Nutrition/Dietetics 

  Metabolism 

  Biology, Molecular 

  Biosynthesis 

  Hormones 



National Institute of Diabetes and Digestive and Kidney Diseases

National Heart Lung and Blood Institute

National Institute of Child Health and Human Development



PURPOSE



The National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK), the National Heart Lung and Blood Institute (NHLBI), and the

National Institute of Child Health and Human Development (NICHD) are

interested in receiving research grant applications for support of

research on dietary factors that control or regulate specific molecular

and genetic functions.  Applications covering a broad range of

activities in this area, including both basic and clinical research,

are encouraged. It is expected that regardless of approach, all studies

will be focused on normal and/or abnormal control of gene regulation

and expression.  This type of announcement is issued in order to

encourage investigator-initiated research projects in these areas of

special programmatic interest.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieve the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This program

announcement, Nutrient Influence on Gene Regulation and Expression, is

related to the priority areas focusing on the roles of specific dietary

factors in the etiology and prevention of chronic diseases and obesity.

Potential applicants may obtain a copy of "Healthy People 2000" (Full

Report:  Stock No 017-001-00474-0) or "Healthy People 2000" (Summary

Report:  Stock No 017-001-00473-1) through the Superintendent of

Documents, Government Printing Office, Washington, DC 20402-9325

(telephone 202-783-3238)



ELIGIBILITY REQUIREMENTS



Applications may be submitted by domestic and foreign, 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 Foreign

institutions are not eligible for the First Independent Research

Support and Transition (FIRST) Award (R29).  Applications from minority

individuals and women are encouraged.



MECHANISMS OF SUPPORT



Support of this program will be by research project grants (R01) and

FIRST Awards (R29).



RESEARCH OBJECTIVES



The National Institutes of Health (NIH) supports basic and clinical

studies related to the requirements, bioavailability, and metabolism of

nutrients and other dietary components at the organ, cellular, and

subcellular levels in normal and diseased states Specific areas of

research interest include the understanding of the physiological,

biochemical and molecular functions and mechanisms of

action/interaction of nutrients within the body.



This announcement is intended to stimulate research on dietary factors

and related metabolic interactions that have direct or indirect

nutrient influence on specific gene regulation and expression.  This

would require interdisciplinary efforts focusing on interactions of

nutrition, molecular biology, and metabolism.  Recent studies indicate

that this is an emerging area, rich with opportunities, but in need of

additional support for further development of research efforts It

appears that nutritional factors, e.g., various vitamins regulated via

dietary intake can interact with other regulatory networks, such as

tissue-specific, developmental, and hormonal factors, as well as

dietary fat or carbohydrate, to regulate gene expression.  Other

studies have demonstrated regulation of apoprotein gene expression by

sucrose-rich diet, nutritional regulation of gene expression in

lipogenesis, and suppression of fatty acid synthase transcription by

polyunsaturated fatty acids.  More advanced studies focus on dietary

protein control of intestinal hormone gene expression.  Significant

regulation appears to be at the level of transcription, with controlled

modulation of messenger RNA levels.  However, basic mechanisms

underlying the influence of dietary factors and related metabolites on

gene transcription need further study.  In addition to studies focusing

on mechanisms controlling gene regulation by dietary factors, support

is also needed for work on the interactions between genetic factors and

nutrition.  In particular, work is encouraged on mechanisms influenced

by hyper- and hypo-responsiveness to diet.  This may be critical in

evaluating outcomes of dietary therapy regimens.  Other, specific

examples of research objectives appropriate for inclusion in

applications responsive to this program announcement include:



o studies on retinoic acid regulation of adipocyte gene expression;



o studies of dietary antioxidant/oxidant factors that affect DNA

structure and function;



o studies on influence of cholesterol and triglyceride levels in

regulation of LDL receptor gene and apolipoprotein gene expression in

the liver and GI tract;



o studies on nutrient control of lipoprotein lipase gene expression;



o studies of factors that mediate the protein synthetic response to

nutrient intake;



o studies on interactions of vitamins and other dietary factors with

nuclear receptors;



o studies of gastrointestinal hormone gene regulation by specific

nutrients;



o studies of dietary factors controlling expression of transferrin

receptor and other proliferation-related genes



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical

research grants and cooperative agreements are required to include

minorities and women in study populations so that research findings can

be of benefit to all persons at risk of the disease, disorder or

condition under study; special emphasis must be placed on the need for

inclusion of minorities and women in studies of diseases, disorders and

conditions that disproportionately affect them.  This policy is

intended to apply to males and females of all ages.  If women or

minorities are excluded or inadequately represented in clinical

research, particularly in proposed population-based studies, a clear

compelling rationale must be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of the

study.  This information must be included in the form PHS 398 in

Sections 1-4 of the Research Plan AND summarized in Section 5, Human

Subjects.  Applicants are urged to assess carefully the feasibility of

including the broadest possible representation of minority groups.

However, NIH recognizes that it may not be feasible or appropriate in

all research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for studies

on single minority population groups must be provided.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology, prevention

(and preventive strategies), diagnosis, or treatment of diseases,

disorders or conditions, including but not limited to clinical trials.



The usual NIH policies concerning research on human subjects also

apply. Basic research or clinical studies in which human tissues cannot

be identified or linked to individuals are excluded.  However, every

effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.



Peer reviewers will address specifically whether the research plan in

the application conforms to these policies. If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the selected

study population is inadequate, it will be considered a scientific

weakness or deficiency in the study design and will be reflected in

assigning the priority score to the application.



Applications for clinical research submitted to NIH are required to

address these policies.  NIH funding components will not award grants

or cooperative agreements that do not comply with these policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS 398

(rev. 9/91) and will be accepted at the standard application deadlines

as indicated in the application kit.



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research Resources

may wish to identify the GCRC as a resource for conducting the proposed

research. In such a case, a letter of agreement from either the GCRC

program director or Principal Investigator must be included with the

application.



Application kits are available at most institutional business offices

and may be obtained from the Office of Grants Inquiries, Division of

Research Grants, National Institutes of Health, Westwood Building, Room

449, Bethesda, MD 20892, telephone 301/496-7441.  The title and number

of the announcement must be typed in line 2a on the face page of the

application.



The completed original application and five legible copies must be sent

or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892



REVIEW PROCEDURES



Applications will be assigned on the basis of established PHS referral

guidelines.  Applications will be reviewed for scientific and technical

merit by study sections of the Division of Research Grants, NIH, in

accordance with the standard NIH peer review procedures.  Following

scientific-technical review, the applications will receive a second-

level review by an appropriate national advisory council or board.

Applications for supplements to ongoing awards will be reviewed

according to procedures applicable to the mechanism of the ongoing

award.



AWARD CRITERIA



Applications will compete for available funds with all other approved

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 balance among research areas of the announcement



INQUIRIES



Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



Direct inquiries regarding programmatic issues to:



Michael K. May, Ph.D.

Director, Nutrient Metabolism Program

Division of Digestive Diseases and Nutrition

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 3A18A

Bethesda, MD  20892

Telephone: (301) 496-7121

FAX: (301) 402-1278



Direct inquiries regarding fiscal matters to:



Ms. Paulette Badman

Grants Management Specialist

Division of Extramural Activities

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 639

Bethesda, MD  20892

Telephone:  (301) 496-7467

FAX:  (301) 496-9721



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic Assistance

Nos. 93.837, 93.848, and 93.865.  Awards are made under authorization

of the Public Health Service Act, Title IV, Part A (Public Law 78-410,

as amended by Public Law 99-158, 42 USC 241 and 285) and administered

under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR

Part 74.  This program is not subject to the intergovernmental review

requirements of Executive Order 12372 or Health Systems Agency review.



.

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