BASIC RESEARCH ON HEMATOPOIETIC GENE REGULATION

NIH GUIDE, Volume 22, Number 43, November 26, 1993



PA NUMBER:  PA-94-015



P.T. 34



Keywords:

  Hematology 

  Gene Regulation 

  Biology, Cellular 



National Institute of Diabetes and Digestive and Kidney Diseases



PURPOSE



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

research grant applications related to the mechanisms of hemopoietic

gene regulation and of differential gene expression during

hematopoietic cell maturation and differentiation.



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,

Basic Research on Hemopoietic Gene Regulation, 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

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 First Independent Research

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

minority individuals and women are encouraged.



MECHANISMS OF SUPPORT



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.



RESEARCH OBJECTIVES



The National Institute of Diabetes and Digestive and Kidney Diseases

(NIDDK) supports basic and clinical studies related to hematopoiesis

and the process of lineage-specific differentiation of the

hematopoietic stem cell.  These processes are central to the

maintenance of normal blood cell counts, and to the reconstitution of

blood counts following bone marrow insults, such as infections,

radiation and chemotherapy.  An increased understanding of the

specific molecular mechanisms underlying lineage-specific

differentiation processes could enhance our ability to combat

selective cytopenias, and facilitate bone marrow reconstitution

following bone marrow transplantation.



Areas of research interest under this announcement include, but are

not limited to, investigations into the mechanisms of hematopoietic

gene regulation and of differential gene expression during

hematopoietic cell maturation and differentiation.  Of particular

interest is the elucidation of factors such as DNA elements, DNA

binding proteins, nuclear matrix, signal transduction mechanisms,

stromal or cell-surface protein interactions that may contribute to

lineage-specific differentiation by modulation of gene expression.



The alpha- and beta-globin gene clusters serve as examples of an area

of hematopoiesis that has developed greatly in the past few years.

Most of the regions of the human chromosomes containing the genes for

hemoglobin, defective in Cooley's anemia and sickle cell disease

patients, have been sequenced.  The characterization of relevant DNA

regions and DNA-binding proteins is well along.  The role of the DNA

within the genes, as well as in the genetic regions that control the

DNA, is now understood to a considerable extent.  This information

has been of considerable value in explaining the normal developmental

control of these genes, as well as the abnormal states that exist in

the hemoglobin disorders.  Regions of DNA linked to both clusters of

hemoglobin genes determine developmental expression, and may be

intimately involved in the switch in hemoglobin formation which

occurs at the time of birth in humans and in many animals.  Other

regulatory factors, either closely linked to genes or on other

chromosomes, have been found to control the expression of the genes.

Much still remains to be learned about gene regulation and switching

of expression from one gene to another at various stages of human

development, including the mechanism of action of drugs such as

hydroxyurea and butyrate, which have been shown to enhance fetal

hemoglobin formation, thus lending themselves as possible therapeutic

agents for the globin gene disorders.



The recent cloning of the gene for the hormone erythropoietin and the

gene for the erythropoietin receptor, for humans and other species,

has opened up the study of this aspect of the erythroid component of

hematopoiesis.  The cloning of other cytokines and their receptors

continues rapidly, as well, promising clarification of many aspects

of hematopoiesis, as well as providing other drugs for clinical use.

The molecular mechanisms of these hormone-cell interactions are being

studied at the level of receptor binding, internalization, signal

transduction, and apoptosis.  Similarly, new techniques using cell

surface molecules and monoclonal antibodies, are allowing

identification of various precursor cell populations, including cells

which may constitute the hypothetical totipotent hematopoietic stem

cell.  Characterization and preparation of these stem cell and

precursor cells in large quantities would be of major importance in

the application of this new knowledge to clinical situations.



New techniques including transgenic animal expression systems, "knock

out" animal models (frequently using embryonal cells), PCR assays,

homologous genetic recombination, transient and stable cell

expression systems, and YAC and other large DNA cloning vectors, are

allowing the field of molecular hematopoiesis to develop very

rapidly.  Whereas much of the previous work has used mouse and other

animal models, these new techniques are facilitating more direct

analyses of human genes and cells.



This Program Announcement is intended to stimulate a broad range of

new research programs in the general area of regulation of genetic

processes involved in hematopoietic cell differentiation.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



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 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.



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.



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.  Application kits are

available at most institutional offices of sponsored research and may

be obtained from the Office of Grants Information, Division of

Research Grants, National Institutes of Health, Westwood Building,

Room 449, Bethesda, MD 20892, telephone 301/435-0714.  The title and

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

of the application.



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.



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.



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 CONSIDERATIONS



Although this is a Program Announcement sponsored by the National

Institute of Diabetes and Digestive and Kidney Diseases, the National

Heart, Lung, and Blood Institute also has an interest in the subject

matter of this PA.  Other Institutes/Centers of the NIH also may have

an interest.  Applications will be assigned to the most appropriate

Institute/Center on the basis of established Public Health Service

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:



David G. Badman, Ph.D.

Division of Kidney, Urologic, and Hematologic Diseases

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 3A-05

Bethesda, MD  20892

Telephone:  (301) 594-7541



Direct inquiries regarding fiscal matters to:



Ms. Trude McCain

Division of Extramural Activities

National Institute of Diabetes and Digestive and Kidney Diseases

Westwood Building, Room 649

Bethesda, MD  20892

Telephone:  (301) 594-7543



AUTHORITY AND REGULATIONS



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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