NIH GUIDE, Volume 22, Number 11, March 19, 1993

PA NUMBER:  PA-93-065

P.T. 34



  Biology, Cellular 


National Institute of Diabetes and Digestive and Kidney Diseases


The purpose of this Program Announcement (PA) is to encourage research

grant applications related to nutrient antioxidants, their roles and

interactions in cellular mechanisms, and their protection against

cellular damage.


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 PA,

Nutrient Antioxidants, Cellular Metabolism and Function, is related to

the priority area of diabetes and other chronic disorders.  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



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 First Independent Research Support

and Transition (FIRST) (R29) awards.  Applications from minority

individuals and women are encouraged.


Support of this program will be primarily by research project grants

(R01) and FIRST awards (R29).  Deadlines for new grants are February 1,

June 1, and October 1, and for competing and revised grants are March

1, July 1, and November 1.  Because the nature and scope of the

research applications submitted in response to this Program

Announcement may vary, it is anticipated that the size of award will

vary also; however, the average size is estimated to be approximately

$200,000, total costs.


The National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) 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.  Areas of research interest include the

understanding of the physiological, biochemical, and molecular factors

and mechanisms of action/interaction of nutrients, including nutrient

antioxidants, within the body.

Nutrient antioxidants are now believed to protect against free radical

cellular damage caused by excessive oxidative reactions.  Examples of

damage caused by excessive concentration of various forms of oxygen and

of free-radical activity include polysaccharide depolymerization

(carbohydrate damage), oxidation and inactivation of

sulfhydryl-containing enzymes (protein damage), and separation of DNA

strands, cross-linkage, or base hydroxylation leading to mutations and

inhibition of genes that are responsible for protein, nucleotide, and

fatty acid synthesis (nucleic acid damage).  Perhaps the best

understood mechanism of free radical-induced cell injury relates to

peroxidation of polyunsaturated fatty acids in organelles and plasma

membranes (lipid damage).  The effects of several nutrient antioxidants

at various steps in lipid peroxidation have been well-studied.

Nevertheless, the overall role of antioxidants in cellular regulation

and the balance between antioxidative and oxidative processes in cells

under various states need further study.

Oxidized and peroxidized compounds may be causally related to a variety

of chronic diseases.  For example, free radicals appear to play a role

in the promotion and/or initiation of some cancers (such as breast,

cervical, lung, and gastrointestinal cancers), cardiovascular diseases,

cataracts, and degenerative diseases of the central nervous system.  In

addition, there is substantial evidence that indicates a role of free

radical-induced cell injury in the aging process itself.  While the

list of chronic diseases believed to have free radical or oxidant

involvement is growing, in most cases it remains unclear whether this

involvement is a cause or a result of the disease.  However,

epidemiological and clinical studies have suggested that nutrient

antioxidants may reduce the risk of these diseases.  Vitamin C, vitamin

E and/or beta-carotene and other carotenoids appear to be most

effective.  Other nutrients (zinc, copper, manganese, and selenium)

associated with antioxidant enzymes may also be involved in protection

against degenerative and chronic diseases since dietary deficiencies of

minerals needed for synthesis of antioxidant enzymes can have a

deleterious effect on enzyme formation.  Relevant mechanisms focusing

on the metabolism of nutrient antioxidants as well as their effect on

cellular functions and metabolic processes need further study.  In

addition, it now appears that the status of nutrient antioxidants may

be influenced by other nutrient factors.  For example, increased levels

of omega-3 fatty acids in the diet appear to result in a decrease in

vitamin E (alpha-tocopherol) levels.  Such interactions and their

metabolic consequences need to be delineated at the cellular and

subcellular levels.  The mechanisms, location, and interactive

metabolic effects of supplemental nutrient antioxidants on

gastrointestinal absorption and transport, and other cellular processes

need further study, for individual nutrients as well as for their

complementary and synergistic roles.

Other Institutes that have significant interests in nutrient metabolism

and antioxidant research include the National Institute on Aging (NIA),

the National Cancer Institute (NCI), the National Heart, Lung and Blood

Institute (NHLBI), the National Eye Institute (NEI), the National

Institute of Environmental Health Sciences (NIEHS), the National

Institute of Neurological Diseases and Stroke (NINDS), the National

Institute of General Medical Sciences (NIGMS), the National Institute

of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the

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

Areas of research of particular interest to the NIDDK focus on the

normal and abnormal metabolism of nutrient antioxidants and resultant

effects on oxidative processes (as well as other metabolic activities)

within the cell.  Complementary functions and the synergistic

interactions between nutrient antioxidants are also of special

interest, especially at those levels which may exceed normal

nutritional requirements.  Also of great importance are studies that

focus on determination of proper balances between nutrient antioxidants

and beneficial and deleterious levels of free radicals.

Other specific examples of research objectives appropriate for

inclusion in applications responsive to this program announcement

include, but are not limited to, studies on:

o  nutrient antioxidant effects on impaired cellular energy systems

including effects on the mechanisms surrounding glycolytic synthesis of

ATP and on oxidative phosphorylation after free radical impairment;

o  nutrient antioxidant prevention of oxidant damage to cellular DNA,

including effects on participation of the hydroxyl radical, DNA base

hydroxylation by various oxidants, DNA damage by products of lipid

peroxidation, and ultimate effects on mutagenesis and cell death;

o  nutrient antioxidant influence on peroxidation of polyunsaturated

fatty acids in cellular organelles and plasma membranes;

o  nutrient antioxidant role in prevention of oxidation of

sulfhydryl-containing enzymes and in prevention of polysaccharide


o  influence of nutrient antioxidants, including interaction with other

dietary factors, on gastrointestinal absorption, transport and other

cellular functions.

While the major emphases in this effort will be on vitamins C and E,

and on beta-carotene and other carotenoids, research support will not

be limited to these antioxidants.  Studies on nutritional co-factors of

antioxidant enzymes are also important because dietary deficiencies of

minerals needed for enzyme synthesis can have a deleterious effect on

proper oxidant/antioxidant balance and subsequent extent of

free-radical activity.  Furthermore, the interactive and synergistic

effects of all nutrient antioxidants will be a critical area of






NIH policy is that applicants for NIH 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


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


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.

All 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.


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.  If so, a letter of agreement from either the GCRC program

director or Principal Investigator could be included with the


Application kits are available at most institutional offices of

sponsored research 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 this 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**

Applications for R29 awards must include at least three letters of

reference attached to the face page of the original application.

Applications submitted without the required number of reference letters

will be considered incomplete and will be returned without review.


Applications will be assigned to initial review groups and

Institutes/Centers 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



Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding


o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement


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.

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 (594-7520 after 3/26/93)

FAX:  (301) 402-1278

Direct inquiries regarding fiscal matters to:

Ms. Paulette Badman

Division of Extramural Activities

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 639

Bethesda, MD  20892

Telephone:  (301) 496-7467 (594-7543 after 3/26/93)

FAX:  (301) 496-9721 (594-7594 after 3/26/93)


This program is described in the Catalog of Federal Domestic Assistance

No. 93.848.  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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