MECHANISMS OF FETAL HEMOGLOBIN GENE SILENCING FOR TREATMENT OF SICKLE CELL 
DISEASE AND COOLEY'S ANEMIA

RELEASE DATE:  February 25, 2002

RFA:  RFA-HL-02-015

PARTICIPATING INSTITUTES AND CENTERS (ICs):

National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov) 

LETTER OF INTENT RECEIPT DATE:  June 14, 2002
APPLICATION RECEIPT DATE:       July 12, 2002

THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The National Heart, Lung, and Blood Institute (NHLBI) invites applications 
for new research grants to identify mechanisms of fetal hemoglobin (gamma-
globin) gene silencing during normal human development, mechanisms of 
variable silencing in adults, and to develop therapeutic approaches to 
inhibit silencing. Focused investigations of the mechanisms of action of cis- 
and/or trans-acting elements important in gamma-globin gene silencing are 
especially encouraged. Secondary goals are the early evaluation of 
pharmacologic, or gene-based approaches to interfere with silencing, and 
studies addressing the mechanistic basis of variable silencing that might 
account for the variable levels of residual gamma-globin seen in adults.  A 
renewed effort to understand the molecular basis of fetal hemoglobin 
silencing will facilitate the development of new gene-based therapeutic 
approaches to inhibit silencing, in order to increase fetal hemoglobin in red 
blood cells, and thus to cure beta-chain hemoglobinopathies such as sickle 
cell disease and Cooley's anemia. 

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 inhibit the 
variable, normal shutdown of gamma-globin chain synthesis (and thus fetal 
hemoglobin tetramers) that occurs 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). The two gamma-globin genes on human chromosome 11 are each 
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 mechanisms of 
gamma-globin gene silencing (the focus of this RFA), as well as mechanisms of 
gamma-globin gene activation will allow the development of therapeutic 
methods for net fetal hemoglobin induction. Gamma-globin gene activation was 
the focus of the NHLBI RFA HL-01-013 (Transactivation of Fetal Hemoglobin 
Genes for Treatment of Sickle Cell Disease and Cooley's Anemia)funded in 
FY2001. Ultimately, the desired therapeutic modalities could in principle act 
either through inhibition of gamma-globin gene silencing, and/or activation 
of gamma-globin gene transcription. 
   
With regard to our understanding of gamma-globin gene silencing per se, only 
limited progress has been made in the recent past. In spite of much effort 
over the last twenty years, little is known about the precise mechanisms by 
which both gamma-globin genes, or more generally all beta-like genes in the 
beta-globin locus found on chromosome 11, are silenced during human 
development.  Much more work is needed, and a renewed, expanded research 
effort is necessary to first clarify mechanisms of silencing, and 
subsequently to enable the development of therapeutics based on the 
inhibition of silencing.  It is commonly believed that both autonomous 
silencing, and locus-specific gene competition mechanisms may be operative 
for gamma-globin genes.  In the former, upstream and downstream regions of 
the gene itself are sufficient to direct silencing, as has been demonstrated 
in the zeta-globin gene on human chromosome 16.  No other genes from the 
locus are needed for silencing to occur. In contrast, for the gene 
competition mechanism, gene activity is inversely dependent on the activity 
of neighboring genes in the locus, which likely depend on proximity to the 
LCR. Interestingly, there is evidence for autonomous silencing of gamma-
globin genes, but not for the downstream beta-globin gene.  While results 
from the recent literature hint that chromatin structure (modifiable by 
acetylation and methylation), DNA topology (looping), and numerous trans-
acting factors might play key roles in gamma-globin silencing, a convincing 
body of evidence in favor of any specific molecular mechanism of gamma-globin 
silencing has not yet been produced.

The cis-acting elements that have been implicated in gamma-globin silencing 
include those located 200 base pairs (bp) upstream of the transcription start 
site, polymorphisms located in the promoter itself, and an element 750 bp 
downstream of the A-gamma-globin gene. In addition, at least nine trans-
acting factors have been identified that bind to the gamma-globin promoter 
region. Much of the prior work in the globin gene silencing area has been 
focused on the study of a class of clinical syndromes known as hereditary 
persistence of fetal hemoglobin (HPFH), where hemoglobin isoform switching is 
altered in the adult, giving rise to higher than normal levels of fetal 
hemoglobin. More than 60 human HPFH mutations are known, and they can be 
subdivided into deletional and non-deletional subclasses. Most of the non-
deletional HPFH mutations occur in transcription factor binding sites- they 
create new binding sites, or they destroy existing ones. HPFH clinical 
syndromes can also be subdivided into pancellular and heterocellular classes, 
depending on the distribution of red blood cells with elevated fetal 
hemoglobin (F cells).  In addition, their relative effects on the two gamma-
globin genes are different (despite that the fact that the DNA sequence of 
the two gamma promoters is identical). Unfortunately, attempts to translate 
knowledge of the existence of HPFH mutations into mechanisms of gamma-globin 
silencing have either not been completed, or have been unsuccessful. 
Characterization of the DNA sequences and proteins involved in the gamma-
globin gene silencing process have been only partially successful, and a 
therapeutically useful mechanistic picture has yet to emerge. Much remains to 
be learned about the mechanism by which HPFH mutations lead to increased 
levels of F cells in adults. 

The research scope of this RFA (see below for specific examples) will include 
confirmation of the roles in silencing of previously implicated cis- and 
trans-acting elements, as well as the identification of new cis-acting 
factors, and new trans-acting 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 hematopoietic and 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 
(PGAs), in particular those expressed sequences, or mutant mouse strains 
associated with increased levels of fetal hemoglobin-containing red blood 
cells (i.e. 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 
silence fetal hemoglobin expression in post-natal life. Potential target 
elements 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 the roles of known trans-acting factors in gamma-globin gene 
silencing via clear demonstration that the factor gene or protein silences a 
gamma-globin gene 

o identification of new cis-acting elements critical for gamma-globin silencing

o identification of cis- or trans-acting factors that contribute to the 
variable silencing of gamma-globin genes seen in adults 

o investigation of the specificity of the silencing activity linked to a 
given trans-acting factor (are other genes silenced, or is the silencing 
effect gamma-globin specific?)

o investigation of the mechanism of action of a validated gamma-globin 
silencing protein 

o investigation of the mechanism of induction/regulation of the structural 
gene for a validated gamma-globin silencing protein
 
o gene discovery for new, unknown silencing 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 trans-
acting silencing factors with respect to mechanism of action, and/or 
mechanism of induction of the structural gene for the silencing protein

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

o identification of drugs or development of genetic strategies that modulate 
the activity of validated gamma-globin silencing proteins, and follow-up 
demonstration of fetal hemoglobin modulation in model systems of SCD or CA 

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

MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) Individual Research 
Project Grant (R01) award mechanism.  As an applicant you will be solely 
responsible for planning, directing, and executing the proposed project.  
This RFA is a one-time solicitation.  This RFA is a one-time solicitation.  
Future unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures. The anticipated 
award date is April 1, 2003.

This RFA uses just-in-time concepts.  It also uses the modular budgeting 
format.  (see https://grants.nih.gov/grants/funding/modular/modular.htm).

FUNDS AVAILABLE 

The National Heart, Lung, and Blood Institute (NHLBI) intends to commit 
approximately $2 million total costs in FY2003 to fund 6 to 8 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 $200,000 (8 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 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. 

ELIGIBLE INSTITUTIONS

You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
					
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.   

SPECIAL REQUIREMENTS 

Exclusions

To be responsive to this RFA, applications must include gamma-globin genes at 
some stage of their research plan.  For example, applications that include 
only beta-globin genes, or other non-gamma-globin genes will be judged 
unresponsive to this RFA.  Applicants must adequately demonstrate the 
physiologic relevance of the proposed research to silencing of the human 
gamma-globin gene.

This RFA program is focused on mechanisms of gene silencing per se, as 
applied to gamma-globin genes. To be responsive to this RFA, applications 
should propose studies focused on processes of gene silencing, i.e. the 
process of turning off the expression of an active gene. For example, 
proposals to identify cis-acting elements of gamma-globin gene activation 
during human development will not be responsive to this RFA. 

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

Grantees Meetings 

Upon initiation of the program, the NHLBI 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, to be held in Bethesda, Maryland.  These meetings will be 
held jointly with those for the NHLBI RFA HL-01-013 (Transactivation of Fetal 
Hemoglobin Genes for Treatment of Sickle Cell Disease and Cooley's Anemia) 
funded in FY2001. 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.

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into three 
areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Greg Evans, Ph.D. 
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 10152, MSC 7950
Bethesda, Maryland  20817-7950
Telephone:  (301) 435-0055
FAX:  (301) 480-0868
Email:  EvansG@nih.gov

o Direct your questions about peer review issues, letters of intent, and 
application procedures to:

Anne Clark, Ph.D.
Chief, Review Branch
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) 480-0730
Email:  ClarkA@nhlbi.nih.gov

o Direct your questions about financial or grants management matters to:

Marsha Mathis
Grants Operation Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Room 7158, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0170
FAX:  (301) 480-3310
Email:  MathisM@nhlbi.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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. Such letters also are helpful to staff in making a 
preliminary assessment of responsiveness to the RFA.
 
The letter of intent is to be sent by June 14, 2002 to:

Anne Clark, Ph.D.
Chief, Review Branch
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) 480-0730
Email:  ClarkA@nhlbi.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at 
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 
Email:  GrantsInfo@nih.gov.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at 
https://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
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 RFA label is also available at:  
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: 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 as well 
as all five collated sets of Appendix material must be sent to:

Anne Clark, Ph.D.
Chief, Review Branch
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) 480-0730
Email:  ClarkA@nhlbi.nih.gov

Please note that applications delivered by individuals are no longer 
accepted; all applications must either come via courier delivery or the USPS 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).
 
APPLICATION PROCESSING: 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.

Principal investigators should not send supplementary material without first 
contacting the Scientific Review Administrator (SRA). The SRA will be 
identified in the letter sent to you indicating that your application has 
been received. If you have not received such a letter within three weeks 
after submitting the application, contact Dr. Anne Clark at the address 
listed under inquiries. 

PEER REVIEW PROCESS  
 
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:

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the NHLBI National 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 your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your 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, you 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 your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
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?  Do you acknowledge potential problem areas and consider 
alternative tactics?

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  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.

o INCLUSION:  The adequacy of plans to include subjects from both genders, 
all racial and ethnic groups (and subgroups), and children as appropriate for 
the scientific goals of the research.  Plans for the recruitment and 
retention of subjects will also be evaluated. (See Inclusion Criteria 
included in the section on Federal Citations, below)

o BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    June 14,  2002
Application Receipt Date:         July 12,  2002
Peer Review Date:                 October/November,  2002
Council Review:                   February 6-7,  2003
Earliest Anticipated Start Date:  April 1,  2003

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.
 
REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH:  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 clinical research projects unless a 
clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001 
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
The NIH maintains a policy 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 is available at  
https://grants.nih.gov/grants/funding/children/children.htm.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:  NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at 
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned 
without review.

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.NIH has providedguidance at 
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

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.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

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 
RFA 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.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.839 and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  

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 described at https://grants.nih.gov/grants/policy/policy.htm 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the 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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