PILOT AND FEASIBILITY PROGRAM IN HEMATOLOGIC DISEASES

RELEASE DATE:  August 16, 2004
 
PA NUMBER:  PA-04-144

March 2, 2006 (NOT-OD-06-046)   Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. Replacement R21 (PA-06-150) funding 
opportunity announcement has been issued for the submission date of June 1, 2006 
and submission dates thereafter. 

See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and 
AIDS-related R03 and R21 Applications.

EXPIRATION DATE:  March 2, 2006

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION: 
National Institutes of Health (NIH) 
 (http://www.nih.gov)
 
COMPONENT OF PARTICIPATING ORGANIZATION: 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER:  93.849

This Program Announcement (PA) replaces PA-01-128
http://grants.nih.gov/grants/guide/pa-files/PA-01-128.html which was 
published in the NIH Guide on August 14, 2001.

THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Submitting an Application
o Supplemental Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) of the 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
invites investigator-initiated applications through the 
Exploratory/Developmental Grant (R21) application mechanism from 
investigators with research interests related to hematology and that serve 
the mission of NIDDK.  The primary intent of this initiative is to encourage 
new, exploratory and developmental research projects by providing support for 
the early stages of their development. For example, such projects could 
assess the feasibility of a novel area of investigation or a new experimental 
system that has the potential to enhance health-related research. These 
studies may involve considerable risk but may lead to advances in a 
particular area, or to the development of novel techniques, agents, 
methodologies, models or applications that could have major impact on the 
field of hematologic research. This Program Announcement (PA) replaces 
PA-01-128 http://grants.nih.gov/grants/guide/pa-files/PA-01-128.html which was 
published in the NIH Guide on August 14, 2001.

The R21 is intended to foster research by newly independent investigators or 
by established investigators developing a new line of research.  Information 
thus obtained would allow subsequent submission of R01 applications focusing 
on research problems relevant to the study of hematologic diseases and their 
complications.  Applications for R21 awards should describe projects distinct 
from those supported through the traditional R01 mechanism. For example, 
long-term projects, or projects designed to increase knowledge in a well-
established area will not be considered for R21 awards.   

RESEARCH OBJECTIVES

Appropriate topics for investigation may include, but are not limited to:

o  Setting up reliable and convenient clonogenic assays for stem cell 
populations in fetal and adult hematopoietic tissues with the purpose of 
using such assays to monitor the purification and characterization of 
hematopoietic stem cells.  Cell populations may be obtained from model 
organisms as well as from humans.

o  Assembly of mRNA and protein expression profiles in recovered progenitor 
cell populations derived from fetal and adult normal tissues.

o  Assessment of the contribution of various cell populations to creating and 
maintaining adult stem cell niches in tissues.

o  Manipulations of gene expression in adult hematopoietic stem cells and 
their immediate descendants in an effort to predict changes in phenotype.

o  Examination of the mechanisms of trafficking, homing, and engraftment of 
adult hematopoietic stem cells.

o  Development of novel approaches to manipulate purified cells and/or the 
host to facilitate production of desired cell types from adult hematopoietic 
stem cell transplantation.

o  Evaluation of the relative role that genetic modifiers and the environment 
make in determining the phenotypic variation in E/Beta thalassemia and other 
thalassemias.

o  Delineation of the structure-function relationships of the beta-globin 
locus control region (LCR).

o  Determination of the molecular mechanism(s) by which agents induce fetal 
hemoglobin production with the goal of developing more efficient inducers.

o  Examination of the mechanism(s) involved in globin gene silencing and 
development of approaches for inhibition of silencing, including, but not 
limited to use of genetic insulators.

o  Identification of the entities involved with the transport of iron out of 
reticuloendothelial cells, and the mechanisms of iron overload. 

o  Determination of the potential role red blood cell transmembrane proteins 
play as elements important for the organization and dynamics the membrane 
architecture; development of new approaches to study the role of cytoskeletal 
architecture in cell regulation; better systems for gene knock out/knock in 
with isoforms, ways to assess role of localization/sequestration in in vivo 
regulation

o  Examination of the mechanisms leading to congenital anemias, such as 
Diamond Blackfan anemia or Fanconi anemia.

o  Molecular dissection of hematopoietic growth factor signaling mechanisms, 
for example, erythropoietin binding to its receptor and subsequent downstream 
events.

o  Characterization of the genetic and molecular pathways involved in the 
differentiation of human embryonic stem cells into the cells of the 
hematopoietic lineage.

MECHANISM(S) OF SUPPORT 

This PA will use the NIH Exploratory/Developmental Grant (R21) award 
mechanism.  As an applicant, you will be solely responsible for planning, 
directing, and executing the proposed project. R21 applications may request 
up to $275,000 over a two-year period. Direct costs exceeding this amount 
because of F&A costs to subcontracts to the project are not subject to the 
cap. 

This PA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  This program does not 
require cost sharing as defined in the current NIH Grants Policy Statement at 
http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part2.htm.

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 Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations

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.  

WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Terry Rogers Bishop, Ph.D.
Erythroid Cell Genomics Program Director
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 619
Bethesda, MD  20892-5458
Telephone:  (301) 594-7721
FAX:  (301) 480-3510
Email:  [email protected]

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

Aretina Perry-Jones
Grants Management Specialist
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 716
Bethesda, MD   20892-5456
Telephone: (301) 594-8862
FAX: (301) 594-9523
Email: [email protected] 

SUBMITTING AN APPLICATION

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 D&B number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The D&B number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email: [email protected].

The title and number of this program announcement must be typed on line 2 of 
the face page of the application form and the YES box must box must be 
checked.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SUPPLEMENTAL INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) 
must be followed, with these exceptions:

o  Research Plan

Items a - d of the Research Plan (Specific Aims, Background and Significance, 
Preliminary Studies, and Research Design and Methods) may not exceed a total 
of 15 pages.  Preliminary data are not required but may be included if 
available.  Please note that a Progress Report is not needed; competing 
continuation applications for an exploratory/developmental grant will not be 
accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 
except that no more than five manuscripts, previously accepted for 
publication, may be included. No photographs or color images may be included 
in the appendix that are not also represented within the Research Plan.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:  All investigator 
initiated R21 applications 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 
http://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 
http://grants.nih.gov/grants/funding/modular/modular.htm.

For the NIH Exploratory/Developmental Grant (R21), applicants may request 
direct costs in $25,000 modules, up to a total direct cost of $275,000 for 
the combined two-year award period.      

SENDING AN APPLICATION TO THE NIH:  Submit a signed, typewritten original of 
the application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA 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 a substantial revision of an R21 application already reviewed, 
but such application must include an Introduction addressing the previous 
critique.

Although there is no immediate acknowledgement of the receipt of an 
application, applicants generally are notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group, 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm), will evaluate applications for 
scientific and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by an appropriate national advisory council 
or board.
   
REVIEW CRITERIA

The NIH R21 exploratory/developmental grant is a mechanism for supporting 
novel scientific ideas or new model systems, tools or technologies that have 
the potential to significantly advance our knowledge or the status of health-
related research.  Because the research plan is limited to 15 pages, an
exploratory/developmental grant application need not have extensive 
background material or preliminary information as one might normally expect 
in an R01 application.  Accordingly, reviewers will focus their evaluation on  
the conceptual framework, the level of innovation, and the potential to 
significantly advance our knowledge or understanding.  Reviewers will place 
less emphasis on methodological details and certain indicators traditionally 
used in evaluating the scientific merit of R01 applications including 
supportive preliminary data. Appropriate justification for the proposed work 
can be provided through literature citations, data from other sources, or, 
when available, from investigator-generated data.  Preliminary data are not 
required for R21 applications.    
 
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: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these criteria 
in assigning the application's overall score, weighting them as appropriate 
for each application.  The application does not need to be strong in all 
categories to be judged likely to significantly advance current knowledge and 
thus deserve a meritorious priority score.  

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:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
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).
 
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 will be assessed.  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.  

ADDITIONAL CONSIDERATIONS 

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

AWARD CRITERIA

Applications submitted in response to this PA will compete for available 
funds with all other recommended applications.  The following will be 
considered in making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS

ANIMAL WELFARE PROTECTION:  Recipients of PHS support for activities 
involving live, vertebrate animals must comply with PHS Policy on Humane Care 
and Use of Laboratory Animals 
(http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf), as 
mandated by the Health Research Extension Act of 1985 
(http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA 
Animal Welfare Regulations 
(http://www.nal.usda.gov/awic/legislat/usdaleg1.htm), as applicable.

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
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).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm 

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 "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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines are available at 
http://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. 

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 
http://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 
http://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 http://stemcells.nih.gov/index.asp and at  
http://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, 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. 

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 provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PAR 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.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the  Standards for Privacy of Individually Identifiable Health Information , 
the  Privacy Rule,  on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on  Am I a covered 
entity?   Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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.   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 
PAR is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ 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 
http://grants.nih.gov/grants/policy/policy.htm.

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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