RELEASE DATE:  September 16, 2003
RFA Number:  RFA-HL-04-008

Department of Health and Human Services (DHHS)


National Institutes of Health (NIH)


National Heart, Lung, and Blood Institute (NHLBI)



o Purpose of this RFA
o Research Objectives
o Mechanism(s) 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 Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations


The goal of this initiative is to encourage research into the genetics and basic 
mechanisms of Diamond-Blackfan Anemia and other rare inherited bone marrow 
failure syndromes that have received little attention from the research 
community.  Applications are sought that propose innovative research approaches 
to understand the molecular pathways disrupted in these syndromes. The bone 
marrow failure syndromes covered by this initiative include: Diamond-Blackfan 
anemia, dyskeratosis congenita, Pearson syndrome, severe congenital neutropenia 
(Kostmann syndrome), Shwachman-Diamond syndrome, and congenital amegakaryocytic 



Several human genetic diseases are characterized by bone marrow failure during 
early development, and result in the decreased production of blood cells as well 
as other constitutional abnormalities. Bone marrow failure may affect all 3 
myeloid lineages (erythrocytes, granulocytes, and platelets) such as in Fanconi 
anemia (FA), Dyskeratosis Congenita (DC), and Pearson syndrome (PS).  
Alternatively, a single lineage may be affected, such as the erythroid series in 
Diamond-Blackfan anemia (DBA), granulocytes in Kostmann disease (KS), cyclic 
neutropenia (CN) and Shwachman Diamond syndrome (SDS), or platelets in 
congenital amegakaryocytic thrombocytopenia (CAMT).  

Although recent clinical advances have vastly improved the quality of supportive 
care for these patients, hematopoietic stem cell transplant remains the only 
curative treatment for bone marrow failure.  Only a small fraction 
(approximately 20%) of patients have a suitable sibling transplant donor, and 
even those transplants carry an upfront mortality risk.  Identification of 
biochemical pathways disrupted in these disorders would facilitate the 
development of targeted drug therapies.  

Furthermore, many of these syndromes are associated with an increased risk of 
both hematologic and solid malignancies.  An understanding of the mechanisms 
contributing to marrow failure and cancer development in these patients may be 
broadly applicable to diseases in the general population.  Fanconi anemia, 
another inherited marrow failure syndrome, is a prime example of how studies in 
a rare inherited disorder have shed light on mechanisms contributing to cancer 
in the population at large.

Although rare, these disorders are associated with significant morbidity and 
mortality.  Affected patients suffer from chronic anemia, neutropenia and/or 
thrombocytopenia that are disproportionately demanding on health care resources.  
In many conditions, treatment is empirical or symptomatic, and the recent 
identification of affected genes has to date had little effect on developing 
more rational therapy.  Malignancies are particularly difficult to treat in 
these patients, and the molecular mechanisms contributing to increased cancer 
risk are generally unknown.  Most of the diseases under discussion are rare and 
have therefore not attracted the attention of many investigators.  Little is 
understood about the biochemical mechanisms contributing to these diseases and 
curative therapeutic options are limited despite the recent identification of 
mutant genes. Finally, insights into the mechanism of bone marrow failure are 
likely to lead to greater understanding of the regulation of hematopoiesis, and 
this might translate into more widely applicable therapeutic approaches to 
stimulating specific hematopoietic lineages.

Up until recently, the focus in many of these conditions has been gene 
identification.  Because the diseases are rare and families for the most part 
small, cooperation among investigators is vital for family linkage studies 
unless large families can be identified.  While gene identification has proven 
extremely helpful for diagnostics and carrier detection, unfortunately gene 
identification has not resulted in any therapeutic benefit to date. With the 
possible exception of DC, where dyskerin and telomerase RNA are likely to play 
a role in telomere maintenance and cellular senescence, little is understood of 
the precise role of the other identified genes in hematopoietic failure. By 
encouraging additional translational investigators to study the basic molecular 
mechanisms underlying the marrow failure syndromes, new strategies for targeted 
therapies can be developed.

Examples of Research Areas

The following are some examples of research areas that investigators may 
consider for their applications.  The list is not meant to be exhaustive and 
applicants are encouraged to develop their own ideas.

- Cell biology studies of patient-derived cell lines and blood/marrow/tissue 
samples to establish a cellular phenotype (eg:  cell cycle, apoptosis, DNA 
damage response, telomere maintenance)
- Development of animal models of inherited bone marrow failure syndromes (eg: 
zebrafish, mouse)
- Functional/biochemical characterization of proteins affected in these 
disorders (eg: subcellular localization, response to stimulants/stressors, 
binding partners, structure/function studies)
- Identification of additional genes mutated in these disorders (eg: genome wide 
screens, candidate gene analysis)
- RNA processing, metabolism and ribosome function with regard to these 
- RNAi studies knocking out affected genes and screening for cellular phenotypes 
for these disorders
- DNA chip expression profile studies of the disorders to identify candidate 
pathways involved 
- Small molecule screens to identify potential therapeutic drugs that correct 
the cellular phenotypes identified through the above studies
- Study the potential role of congenital marrow failure genes in bone marrow 
failure or tumorigenesis in the general population

This RFA will use NIH 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.  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 
September 30, 2004. Applications that are not funded in the competition 
described in this RFA may be resubmitted as NEW investigator-initiated 
applications using the standard receipt dates for NEW applications described in 
the instructions to the PHS 398 application.  
This RFA uses just-in-time concepts.  It also uses the modular budgeting format. 
Specifically, if you are submitting an application with direct costs in each 
year of $250,000 or less, use the modular budget format.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at    

Since the total costs for a subcontract or consortium are included in the direct 
cost request, one additional module of $25,000 above the cap may be requested 
for the facilities and administrative costs associated with third party 
agreements.  A module requested for this purpose must be clearly identified in 
the budget justification section of the application, and will be restricted for 
this purpose only at the time of award.


The NHLBI intends to commit approximately $3,000,000 in FY 2004 to fund about 7 
to 9 new grants in response to this RFA. An applicant may request a project 
period of up to five years and a budget for direct costs of up to $250,000 per 
year. Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration 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 
You may submit (an) application(s) if your institution has any of the following 
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, and 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations 

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.   


Exclusions: Applications focused on Fanconi Anemia will not be responsive to 
this RFA, as this area has already received much attention from the scientific 
research community. 

Areas of research must address bone marrow failure syndromes and must address 
research into the genetics and basic mechanisms of Diamond-Blackfan Anemia or 
other rare, inherited bone marrow failure syndromes. These bone marrow failure 
syndromes include: Diamond-Blackfan anemia, dyskeratosis congenita, Pearson 
syndrome, severe congenital neutropenia (Kostmann syndrome), Shwachman-Diamond 
syndrome, and congenital amegakaryocytic thrombocytopenia. 

General Clinical Research Centers
Applications from institutions that have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources (NCRR) 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 the principal 
investigator should be included with the application.
Principal investigators will be required to attend an annual meeting organized 
by the NHLBI.  Please include travel to Bethesda, MD area as part of the budget 

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:

Pankaj Qasba, Ph.D.
Division of Blood Diseases and Resources
National Heart Lung and Blood Institute
6701 Rockledge Dr, MSC 7950
Bethesda MD 20892-7950
301 435 0050 (phone)
301 480 0868 (fax)

o Direct your questions about peer review issues to:

Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7214, MSC-7924
Bethesda, MD  20892, (For Express Mail Use Zip Code 20817)
Telephone:  (301) 435-0270
FAX:  301-480-0730
o Direct your questions about financial or grants management matters to:
Robert Vinson
Division of Extramural Affairs
National Heart, Lung, and Blood Institute 
Building RKL II, Room 7156
Bethesda, MD  20892 - 7926
Telephone:  (301) 435-0166
FAX:  301-480-0166
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 IC staff to estimate the potential review workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning of this 
document.  The letter of intent should be sent to Dr. Anne Clark at the address 

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal 
Identifier when applying for Federal grants or cooperative agreements. The DUNS 
number can be obtained by calling (866) 705-5711 or through the web site at The DUNS number should be 
entered on line 11 of the face page of the PHS 398 form. The PHS 398 is 
available at 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: 
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 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at
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:
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 plus all 
five collated sets of appendix material must be sent to Anne Clark, Ph.D. at the 
address listed under WHERE TO SEND INQUIRIES.

APPLICATION PROCESSING: Applications must be received on or before 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 

Although there is no immediate acknowledgement of the receipt of an application, 
applicants are generally notified of the review and funding assignment within 8 
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.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, it 
is to be prepared as a NEW application.  That is, the application for the RFA 
must not include an Introduction describing the changes and improvements made, 
and the text must not be marked to indicate the changes from the previous 
unfunded version of the application.  

Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NHLBI.  Incomplete applications will not be reviewed.  
If the application is not responsive to the RFA, NIH staff may contact the 
applicant to determine whether to return the application to the applicant or 
submit it for review in competition with unsolicited applications at the next 
appropriate NIH review cycle.

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 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 written critique
o Receive a second level review by the NHLBI National Advisory Council. 

Principal investigators should not sent 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 
Where to Send Inquiries.

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 evaluate the application in order 
to judge the likelihood that the proposed research will have a substantial 
impact on the pursuit of these goals. The scientific review group will address 
and consider each of the following criteria in assigning the application's 
overall score, weighting them as appropriate for each application. 
o Significance 
o Approach 
o Innovation
o Investigator
o Environment

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.
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?
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?
INNOVATION: Does the project employ novel concepts, approaches or methods? Are 
the aims original and innovative? Does the project challenge existing paradigms 
or develop new methodologies or technologies?
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)?
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?  
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:
subjects and protections from research risk relating to their participation in 
the proposed research will be assessed. (See criteria included in the section 
on Federal Citations, below).
to include subjects from 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 in the sections on Federal Citations, below).
CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be 
used in the project, the five items described under Section f of the PHS 398 
research grant application instructions (rev. 5/2001) will be assessed.  
BUDGET:  The reasonableness of the proposed budget and the requested period of 
support in relation to the proposed research.
Letter of Intent Receipt Date: February 17, 2004
Application Receipt Date: March 17, 2004
Peer Review Date: June 2004
Council Review: September, 2004
Earliest Anticipated Start Date: September 30, 2004
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.
HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against these 
risks, the potential benefits of the research to the subjects and others, and 
the importance of the knowledge gained or to be gained. 
DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all 
types of clinical trials, including physiologic, toxicity, and dose-finding 
studies (phase I); efficacy studies (phase II); efficacy, effectiveness and 
comparative trials (phase III).  The establishment of data and safety monitoring 
boards (DSMBs) is required for multi-site clinical trials involving 
interventions that entail potential risk to the participants.   (NIH Policy for 
Data and Safety Monitoring, NIH Guide for Grants and Contracts, June 12, 1998:  
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 "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 
a complete copy of the updated Guidelines are available at   
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.
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
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
HUMAN EMBRYONIC STEM CELLS (hESC):  Criteria for federal funding of research on 
hESCs can be found at and at  
Only research using hESC lines that are registered in the NIH Human Embryonic 
Stem Cell Registry will be eligible for Federal funding 
(see   It is the 
responsibility of the applicant to provide, in the project description and 
elsewhere in the application as appropriate, 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. 
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 provided guidance at
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
AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal 
Domestic Assistance at and is not 
subject to the intergovernmental review requirements of Executive Order 12372 or 
Health Systems Agency review.  Awards are made under the authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 
All awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement. The NIH Grants 
Policy Statement can be found at 
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 

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.