This Program Announcement expires on October 1, 2004 unless reissued.

PILOT AND FEASIBILITY PROGRAM IN HEMATOLOGICAL DISEASES

Release Date:  August 14, 2001

PA NUMBER:  PA-01-128 (see replacement PA-04-144)

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov)

THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  USE THE 
MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 
(REVISION 5/2001) AVAILABLE AT 
http://grants.nih.gov/grants/funding/phs398/phs398.html.  THE 
INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS MUST BE USED WHEN RESPONDING 
TO THIS PA.

PURPOSE

The Division of Kidney, Urologic and Hematologic Diseases (DKUHD) at the 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
invites applications through the exploratory/developmental (R21) grant 
mechanism from investigators with research interests in hematology and 
that serve the mission of NIDDK.  The primary intent of this initiative 
is foster the development of high-risk pilot and feasibility research by 
newly independent or 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 hematological diseases and their complications.  These grants are not 
intended to support or supplement ongoing funded research of an 
established investigator, or to serve as an alternative mechanism of 
support for projects not receiving funding as competitive continuation 
applications.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to increasing the quality 
and years of healthy life and to eliminating health disparities as 
described in the objectives of “Healthy People 2010”.  This document is 
a PHS-led national activity for setting priority areas and is available 
at http://www.health.gov/healthypeople.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit 
organizations, public and private, such as universities, colleges, 
hospitals, and 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.  Furthermore, this mechanism is for 
the support of either new investigators  [defined as independent 
investigators who have not yet held R01, R29, or subprojects of program 
project (P01) or center grants (P50) or equivalent], or established 
investigators entering a new research field or developing a new line of 
research.

MECHANISM OF SUPPORT

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by 
the NIH. Complete and detailed instructions and information on Modular 
Grant applications have been incorporated into the PHS 398 (rev. 
5/2001).  Additional information on Modular Grants can be found at 
http://grants.nih.gov/grants/funding/modular/modular.htm

This program will be supported through the exploratory/developmental 
grant (R21) mechanism. These awards are to demonstrate feasibility and 
to obtain preliminary data testing innovative ideas that represent a 
clear departure from ongoing research interests.  Projects will be 
limited to $100,000 direct costs per year and are limited to two years 
duration.  These grants will not be renewable.  Continuation of projects 
developed under this program will be through the regular research grant 
mechanism (for example, R01).  Responsibility for the planning, 
direction, and execution of the proposed project will be solely that of 
the applicant.  The NIH Grants policy statement applies to these awards.

RESEARCH OBJECTIVES

The NIDDK invites investigator-initiated applications.  Appropriate 
topics for investigation would 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.  Also, such assays may allow factors that 
influence hematopoietic stem cell biological properties to be assayed ex 
vivo.  Cell populations should be obtained from model organisms as well 
as 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 stem cells and their 
immediate descendants in an effort to predict changes in phenotype.

o  Determination of the potential for manipulation of adult stem cells 
by cytokines and other environmental influences.

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

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

o  Investigation of the unexplained interactions of the hemoglobin E 
allele with different beta thalassemia alleles in E/Beta thalassemia, 
including relative rates of synthesis, potential for damage by oxidative 
stress or high body temperatures and oxygen affinity at different levels 
of hemoglobin F.

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

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 molecules involved with the transport of iron 
out of reticuloendothelial cells.  Delineation of the molecular 
mechanism by which recycled iron is loaded onto apo-transferrin and 
determination in which intracellular compartments these events occur in 
order to understand the aberrant iron recycling that occurs in anemia.

o  Determination of the potential role red blood cell membrane proteins 
play as elements important for the organization and dynamics of mitosis, 
the cell cycle or signal transduction.  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 regulation of heme biosynthesis in erythroid 
cells.

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

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 subpopulations must be included in all NIH supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification is provided 
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 

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 policy.

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.

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.  This 
policy announcement is found in the NIH Guide for Grants 
and Contracts Announcement dated June 5, 2000, at the 
following website:  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

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 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.

APPLICATION PROCEDURES

The PHS 398 research grant application instructions and forms (rev. 
5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html are 
to be used in applying for these grants and will be accepted at the 
standard application deadlines (http://grants.nih.gov/grants/dates.htm) 
as indicated in the application kit.  This version of the PHS 398 is 
available in an interactive, searchable PDF format. Although applicants 
are strongly encouraged to begin using the 5/2001 revision of the PHS 
398 as soon as possible, the NIH will continue to accept applications 
prepared using the 4/1998 revision until January 9, 2002. Beginning 
January 10, 2002, however, the NIH will return applications that are not 
submitted on the 5/2001 version.  For further assistance contact 
GrantsInfo, Telephone 301/435-0714, Email: GrantsInfo@nih.gov.

SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS

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 NIH staff.  The research grant application form PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 
is to be used in applying for these grants, with modular budget 
instructions beginning on page 13 of the application instructions.  
Applicants are permitted, however, to use the 4/1998 revision of the PHS 
398 for scheduled application receipt dates until January 9, 2002.  If 
you are preparing an application using the 4/1998 version, please refer 
to the step-by-step instructions for Modular Grants available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

All application instructions outlined in the PHS 398 application kit are 
to be followed, with the following modifications for R21 applications:  

1.  R21 applications will use the “MODULAR GRANT” and “JUST-IN-TIME” 
concepts, with direct costs requested in $25,000 modules, up to the 
total direct costs limit of $100,000 per year. 

2. Although preliminary data are not required for an R21 application, 
they may be included.

3.  Sections a-d of the Research Plan of the R21 application may not 
exceed 15 pages, including tables and figures.  

4.  R21 appendix materials should be limited, as is consistent with the 
exploratory nature of the R21 mechanism, and should not be used to 
circumvent the page limit for the research plan.   Copies of appendix 
material will only be provided to the primary reviewers of the 
application and  will not be reproduced for wider distribution.  The 
following materials may be included in the appendix:

o  Up to five publications, including manuscripts (submitted or accepted 
for publication), abstracts, patents, or other printed materials 
directly relevant to the project.  These may be stapled as sets.
o  Surveys, questionnaires, data collection instruments, and clinical 
protocols.  These may be stapled as sets.
o  Original glossy photographs or color images of gels, micrographs, 
etc., provided that a photocopy (may be reduced in size) is also 
included within the 15 page limit of items a-d of the research plan

The program announcement title and number must be typed on line 2 of the 
face page of the application form and the YES box must be marked.  Mail 
the signed, original, single-sided application, along with five exact, 
single-sided copies and five collated sets of appendix materials 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established Public Health 
Service referral guidelines.  Applications that are complete will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened in accordance with NIH peer review procedures.  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 
applications under review, will be discussed, assigned a priority score, 
and receive a second level review by the appropriate national advisory 
council or board.

Review Criteria

The goals of the supported research are to advance our understanding of 
biological systems, improve the control of disease, improve health care 
services, 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.

(1) 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?

(2) 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)?  Is the investigator a new investigator or an established 
investigator developing a new line of research?

(3) 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?

(4) 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?

(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.

AWARD CRITERIA
Applications will compete for available funds with all other approved 
applications.  The following will be considered in making funding 
decisions:

o  Quality of the proposed project as determined by peer review
o  Availability of funds
o  Program priority

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or 
questions from potential applicants is welcome.  Relevant Scientific 
Program Officers may be identified through the DKUHD webpage at 
http://www.niddk.nih.gov/welcome/org/tables/kuh_table.htm or by making 
direct inquiries to:  

Terry Rogers Bishop, Ph.D.
Erythroid Cell Genomics Program Director
DKUHD
National Institutes of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd, Room 619
Bethesda, MD  20892-5458
Telephone:  (301) 594-7726
FAX:  (301)480-3510
E-mail:  tb232j@nih.gov

Direct inquiries regarding NIDDK fiscal and administrative matters to:

Aretina Perry-Jones
Grants Management Specialist
NIDDK/GMB
6707 Democracy Blvd, Room 716
Room 716, MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8862
FAX:  (301) 594-9523
E-mail:  ap19s@nih.gov

AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance 
No. 93.849.  Awards are made under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public 
Law 99-158, 42 USC 241 and 285) and administered under PHS grants 
policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This 
program is not subject to the intergovernmental review requirements of 
Executive Order 12372 or Health Systems Agency review.  The PHS strongly 
encourages all grant and contract 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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