TRANSACTIVATION OF FETAL HEMOGLOBIN GENES FOR TREATMENT OF SICKLE CELL DISEASE 
AND COOLEY'S ANEMIA

Release Date:  January 17, 2001

RFA:  RFA-HL-01-013

National Heart, Lung, and Blood Institute
 (http://www.nhlbi.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

Letter of Intent Receipt Date:  February 14, 2001
Application Receipt Date:       March 15, 2001

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

PURPOSE

The National Heart, Lung, and Blood Institute (NHLBI) and the National 
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite 
applications for research grants to pursue the unambiguous identification of 
transactivator proteins that regulate the expression of fetal globin chains.  
Both the validation of existing candidate transactivators, and gene discovery 
to identify new ones are encouraged.  Increased understanding of the trans-
acting component of developmental stage-specific hemoglobin isoform switching 
will facilitate the development of new approaches to cure beta-chain 
hemoglobinopathies such as sickle cell disease and Cooley=s anemia.

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 Request for Applications (RFA), 
Transactivation of Fetal Hemoglobin Genes For Treatment of Sickle Cell Disease 
and Cooley=s Anemia, is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at 
http://www.health.gov/healthypeople/.

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. Racial/ethnic minority individuals, women, 
and persons with disabilities are encouraged to apply as Principal 
Investigators.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed 4 years.  This RFA is a one-time solicitation.  Future unsolicited 
competing continuation applications will compete with all investigator-
initiated applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 30, 2001.

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.

FUNDS AVAILABLE 

The National Heart, Lung, and Blood Institute (NHLBI) intends to commit 
approximately $2,500,000 total costs and the National Institute of Diabetes 
and Digestive and Kidney Diseases (NIDDK) intends to commit approximately 
$1,500,000 total costs in FY 2001 to fund 10 to 14 new grants in response to 
this RFA. An applicant may request a project period of up to 4 years and a 
budget for direct costs of up to $250,000 (10 modules) per year. Because the 
nature and scope of the research proposed may vary, it is anticipated that the 
size of each award will also vary. Although the financial plans of the NHLBI 
and NIDDK provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a sufficient 
number of meritorious applications. 

RESEARCH OBJECTIVES

Background

Sickle cell disease (SCD) and Cooley=s anemia (CA; beta-thalassemia) are among 
the most common inherited diseases in humans in the U.S. and worldwide, and 
are associated with a substantial cost burden to the healthcare system. SCD 
was the first human genetic disease to be characterized at the molecular level 
over 50 years ago. It was later shown to result from a point mutation in the 
beta-globin gene that gives rise to a dysfunctional hemoglobin protein, and 
that then becomes manifest clinically in early infancy. CA represents a second 
group of disorders characterized by abnormal beta-globin expression, in 
particular reduced levels of normal beta-globin chains, that result from 
genetic mutations in noncoding regions of the beta-globin gene. As with SCD, 
CA becomes manifest clinically in early infancy. Despite the fact that the 
molecular bases of these so-called beta-chain hemoglobinopathies have been 
known in many cases for decades, there are still no universal cures available 
for these very serious diseases that are associated with significant morbidity 
and in some cases mortality. Hydroxyurea, which does induce the expression of 
fetal hemoglobin, reduces the rate of painful crises in SCD, but is effective 
in only 2/3 of patients. It is largely ineffective for CA.
   
In spite of the slow rate of progress toward universal cures, one strategy 
that has proven to be effective in numerous isolated cases is the induction of 
fetal hemoglobin. The reason that SCD and CA are not clinically manifest 
before early infancy is that the qualitative and quantitative defects in beta-
globin chains are compensated for by gamma-globin chains, that are expressed 
from early embryonic to early infancy stages.  Before early infancy, gamma 
chains complex with alpha chains to form fetal hemoglobin protein tetramers 
that are functionally normal, and that in the case of SCD may actually inhibit 
the polymerization of sickle hemoglobin tetramers (comprised of alpha plus 
beta-S chains). As human development proceeds beyond the early infancy period, 
gamma-globin expression is variably extinguished (see below), and beta-globin 
expression is activated. This then provides a rationale for developing 
pharmacologic or genetic approaches to reinduce gamma-globin chains (and thus 
fetal hemoglobin tetramers) in adult clients with SCD or CA. Currently, 
hydroxyurea and butyrates benefit some patients with SCD or CA, and are 
thought to work at least in part through fetal hemoglobin induction, but they 
do not benefit all patients, and they have limitations due to toxicity and 
route of administration (butyrate). A well-designed epidemiologic study has 
demonstrated that any increase in synthesis of fetal hemoglobin is beneficial 
to the patients with SCD. Clinical observations in patients who are compound 
heterozygotes for a sickle cell gene, and a gene for hereditary persistence of 
fetal hemoglobin (HPFH) or delta-beta-thalassemia indicate that production of 
25 to 30% of total hemoglobin present as fetal hemoglobin can cure SCD. 
Likewise in the case of CA, when the synthesis of fetal hemoglobin is 
abundant, as in the case of delta-beta-thalassemia syndromes, the clinical 
manifestations of the disease are mild. 

Significant progress has been achieved in the last ten years in the 
understanding of the control of globin gene activity during human development 
and the control of fetal hemoglobin synthesis in particular. The existing 
evidence suggests that the fetal globin genes are activated in early embryonic 
development through interactions of transcription factors with sequences of 
the promoters of the gamma-globin genes as well as the sequences of the major 
regulatory element of the beta-globin locus, the locus control region (LCR). 
Gamma-globin genes are turned off in development through a phenomenon of 
autonomous silencing which most likely involves interactions of sequences of 
the promoters of the gamma-globin genes with DNA binding proteins that act as 
suppressors. Gamma-globin genes are not completely turned off, but remain 
active at a low but variable level in adults. It is expected that delineation 
of the exact mechanism of gamma-globin gene activation (the focus of this 
RFA), as well as the exact mechanism of gamma-globin gene silencing will allow 
the development of therapeutic methods of fetal hemoglobin induction. Such 
therapeutic methods could in theory act either through activation of gamma-
globin gene transcription, or through inhibition of gamma-globin gene 
silencing. 
   
It has been shown that a specific transcriptional factor, EKLF (erythroid 
Kruppel-like factor), is responsible for activation of the beta-globin gene. 
It is therefore expected that specific transcriptional factors will be 
responsible for the activation of the gamma-globin genes. Preliminary evidence 
implicates four such candidate factors, designated as SSP (stage-selector 
protein), FKLF (fetal Kruppel-like factor), FKLF-2, and NF-E4 (nuclear factor 
erythroid-4). The research scope of this RFA (see below for specific examples) 
will include confirmation that these four factors are important, as well as 
identification of new regulatory factors through gene discovery efforts. The 
timely use of new genome-wide, or high-throughput methods such as microarrays, 
and of new genomic tools for preliminary gene mapping (e.g. chromosome 
substitution strains of mice), will be encouraged. Also encouraged will be the 
use of new genomic sequence resources such as the draft human and mouse genome 
sequences, and online public databases that will include more and more genomic 
information on red blood cell progenitors in the near future. In addition, 
grantees supported through this RFA may be able in the next several years to 
take timely advantage of the functional genomic resources generated through 
NHLBI=s Programs for Genomic Applications (PGA), in particular those expressed 
sequences, or mutant mouse strains associated with increased levels of fetal 
hemoglobin-containing red blood cells (i.e. so called F cells). The purpose of 
the PGA program, that was initiated in September 2000, is to make functional 
genomic resources related to heart, lung, and blood diseases freely available 
to investigators working in these areas in a timely fashion. It is expected 
that the work supported by this RFA will include as systems of study 
established and primary cell culture, fetal and adult tissue from animal 
models, discarded human fetal tissue, adult human samples and clinical samples 
from patients exhibiting HPFH. Further study of the role of transactivator 
proteins in the phenotypes conferred by the many known human HPFH mutations is 
encouraged. Much remains to be learned about the mechanism by which HPFH 
mutations lead to increased levels of F cells in adults. 

Research supported through this RFA will clarify molecular pathways that 
activate fetal hemoglobin expression. Potential target molecules 
(transactivators) for new approaches to fetal hemoglobin modulation in adults 
will be validated, or identified anew. Finally, these targets will then form 
the foundation of new drug-based and/or genetic approaches to reinduction of 
fetal hemoglobin in adult clients with SCD or CA, to ultimately provide 
universal cures for these common beta-chain hemoglobinopathies.  

Other

The objectives of this program will be optimally met with an interdisciplinary 
team approach. The formation of multidisciplinary teams of investigators 
comprised of individuals with expertise in many of the following areas is 
encouraged: genetics, genomics, biostatistics, gene regulation, and 
hematology. Applications from new investigators, and from established 
investigators working outside of this field are especially encouraged.

Research Scope

Some research topics that will be responsive to this RFA are shown below. 
These are examples only, and potential applicants are encouraged to develop 
other proposals that meet the stated objectives of this program.  Research 
with either animals or human subjects will be responsive to this RFA.

The following are examples of areas of research that will be responsive to 
this RFA:

o validation of existing candidate transactivators (e.g. SSP, FKLK, FKLF-2, 
NF-E4) via clear demonstration that the transactivator gene or protein 
activates a gamma-globin gene 

o investigation of the specificity of induction activity linked to a validated 
gamma-globin transactivator (are other genes coinduced, or is the induction 
gamma-globin specific?)

o investigation of the mechanism of action of a validated gamma-globin 
transactivator

o investigation of the mechanism of induction/regulation of the structural 
gene for a validated gamma-globin transactivator
 
o gene discovery for new transactivator molecules using high-throughput or 
genome-wide methods (e.g. microarrays) and developmental stage-specific probes 
from normal or HPFH tissues; subsequently, validation of these transactivators 
with respect to mechanism of action, and/or mechanism of induction of the 
structural gene for the transactivator

o gene discovery for unlinked genetic modifiers of the expression or activity 
of validated gamma- globin transactivators

o identification of drugs that modulate the expression or activity of 
validated gamma-globin transactivators, and demonstration of fetal hemoglobin 
induction and phenotypic correction in model systems of SCD or CA 

o development of new experimental systems to model the activation of gamma 
globin genes that occurs in human embryonic development, and validation of 
transactivators of gamma-globin in these systems

ALL POTENTIAL APPLICANTS ARE STRONGLY ENCOURAGED TO CONTACT ONE OF THE PROGRAM 
OFFICIALS LISTED UNDER INQUIRIES BELOW TO DISCUSS THE RESPONSIVENESS OF THEIR 
PROPOSALS, IN ADVANCE OF THE RECEIPT DATE FOR THE LETTER OF INTENT.

SPECIAL REQUIREMENTS

Applications that do not specifically include gamma-globin genes to validate 
candidate transactivator proteins at some stage of their research plan will be 
judged unresponsive to this RFA and will be returned to the applicant.  
Applications that include beta-globin genes only will be judged unresponsive 
to this RFA, and will be returned to the applicant.  Applicants must 
adequately demonstrate the physiologic relevance of the proposed research to 
activation of the gamma-globin gene.

Applications proposing human subjects research, animal research, or 
combinations thereof will be responsive to this RFA.

Upon initiation of the program, the NHLBI AND NIDDK will sponsor periodic 
meetings to encourage exchange of information among investigators who 
participate in this program.  This is especially critical if more than one 
group focuses on similar studies, systems, or animal models to avoid 
unnecessary duplication and to expedite progress as a program.  Travel funds 
should be included in the budget modules for the Principal Investigator to 
attend a one day meeting once each year, most likely to be held in Bethesda, 
Maryland.  Applicants should also include a statement in their application 
indicating their willingness to participate in these meetings and to interact 
openly with other study participants in sharing approaches/strategies and 
findings among awardees so as to provide the greatest promise for scientific 
advances from the approved research scope of the awards.

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 sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating 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 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

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/guide/notice-files/not98-024.html.

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

GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS 

All investigators proposing research using human pluripotent stem cells should 
read the National Institutes of Health Guidelines for Research Using Human 
Pluripotent Stem Cells (the Guidelines) published in the Federal Register on 
August 25, 2000 and is available at the following URL address: 
http://stemcells.nih.gov/news/newsArchives/fr25au00-136.asp.

Details on the approval process and the procedures for submitting the required 
documentation of compliance are at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, 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 site.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 14, 2001, a letter of 
intent that includes a descriptive title of the proposed research, the name, 
address, and telephone number of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of the RFA in response to which the application may be submitted.  Although a 
letter of intent is not required, is not binding, and does not enter into the 
review of a subsequent application, the information that it contains allows 
NHLBI staff to estimate the potential review workload and plan the review.

The letter of intent is to be FAXed, mailed, or e-mailed to Dr. Deborah Beebe 
at the address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research and 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.

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 form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications noted below.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

BUDGET INSTRUCTIONS

Modular Grant applications will request direct costs in $25,000 modules, up to 
a maximum total direct cost request of $250,000 (10 modules) per year.  An R01 
grant  application may include research activities that involve institutions 
other than the sponsoring organization, creating a consortium effort.  The 
consortium costs should be included in the direct cost limit ($250,000).  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:

o  FACE PAGE:  Items 7a and 7b should be completed, indicating Direct Costs 
(in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular 
Total Direct plus 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 Form Page 
4-DD of the PHS 398 (rev 4/98).  It is not required nor will it be accepted at 
the time of application.

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

o  NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative 
page.  (See http://grants.nih.gov/grants/funding/modular/modular.htm for 
sample pages).  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 all 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.  For this RFA, the consortium costs should be included in the $250,000 
cost limit.  List the individuals/organizations with whom consortium or 
contractual arrangements have been made, the percent effort of all personnel, 
and the role on the project.  Indicate whether the collaborative institution 
is foreign or domestic.  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 modified 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 three years;
- List selected peer-reviewed publications, with full citation;

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.  All appropriate exclusions must be applied 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 phone number of the individual to 
contact concerning fiscal and administrative issues if additional information 
is necessary following the initial review.

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
affixed to the bottom of the face page of the application.  Type the RFA 
number on the label.  Failure to use this label could result in delayed 
processing of the application such that it may not reach the review committee 
in time for review.  In addition, the RFA title and number must be typed on 
line 2 of the face page of the application form and the YES box must be 
marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to 
allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, and three signed, 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)

At the time of submission, two additional copies of the application must be 
sent to Dr. Deborah Beebe, at the listing under INQUIRIES.

Applications must be received by the application receipt date listed in the 
heading of this RFA.  If an application is received after that date, it will 
be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA 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

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI.  Incomplete and/or non-responsive applications 
will be returned to the applicant without further consideration.

Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below.  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 the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the National Heart, Lung, and Blood Advisory Council and/or the 
National Diabetes and Digestive and Kidney Diseases Advisory Council.

Review Criteria

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 the application 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 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 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.

Schedule

Letter of Intent Receipt Date:  February 14, 2001
Application Receipt Date:       March 15, 2001
Peer Review Date:               June/July, 2001
Council Review:                 September, 2001
Anticipated Start Date:         September 30, 2001

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o  scientific merit (as determined by peer review)

o  availability of funds

o  programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Greg Evans, Ph.D. 
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room10152, MSC 7950
Bethesda, Maryland 20892-7950
Telephone:  (301) 435-0055
FAX:  (301) 480-0868
E-Mail: EvansG@nih.gov

David G. Badman, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 621, MSC 5458

Bethesda, Maryland 20892-5458
Telephone:(301) 594-7717
FAX: (301) 480-3510
E-mail: db70f@nih.gov

Direct inquiries regarding review matters, address the letter of intent, and 
send two copies of the application to:

Deborah Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, Maryland 20892-7924
Telephone: (301) 435-0270
FAX: (301) 480-3541
E-mail: BeebeD@nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Mary S. Page
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7162, MSC 7926
Bethesda, MD 20892-7926
Telephone:  (301) 435-0152
FAX:  (301) 480-3310
E-mail: pagem@nhlbi.nih.gov 

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.839 and 93.848.  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 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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and Human Services (HHS)
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