RELEASE DATE:  July 8, 2003

PA NUMBER: PA-03-150

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 using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. Replacement R21 (PA-06-170) and R01 (PA-06-169), 
funding opportunity announcements have 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

National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK)



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


The National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 
announces a new program designed to stimulate research in erythroid cells.  
The aim of this program is to contribute to a complete description of 
expressed erythroid molecular biological components and to create reagents 
useful for study of the erythroid cell lineages.  Components include genes 
that are expressed in erythroid cells, either during development or during 
differentiation, and the proteins that are translated in erythroid cells, 
potentially with post-translational modifications or subcellular 
localizations that are unique to erythroid cells.  A long range goal of this 
program is to unify genetics and the study of function by facilitating 
characterization of the structure-function relationships between the 
expressed genes in the erythroid lineages and cell morphology, physiology, 
and disease phenotypes. Development of new technologies to facilitate 
applications of this genomic information is also encouraged.  Applicants are 
encouraged to refer to the NIDDK's Progenitor Cell Genome Anatomy Projects at to find current resources that are available.  Synergy 
with existing Progenitor Cell Genome Anatomy Projects is encouraged.



For many years, the erythroid cell has been used as a model system to 
understand molecular genetics, biochemistry, structural membrane biology, 
cell physiology and gene expression.  Given the fact that erythroid cells are 
easy to obtain and that there are relatively few genes expressed, these cells 
provide a model system with which to characterize exactly how the genetic 
program specifies the formation of a particular cell type.  The erythroid 
cell exists as a single, suspended cell, eliminating the complicating factors 
of teasing it away from other cell types and purifying it out of a solid 
matrix.  Likewise, the sheer number of erythroid cells available to harvest 
from a single individual makes it an ideal system to study.  Finally, the 
precursor cells are available through bone marrow harvest and cell 
purification schemes for particular stages of the erythroid lineages have 
been developed for human, rabbit, goat, mouse and most other mammalian 

The relatively lower numbers of expressed sequences in erythroid cells 
facilitate studies to measure basic molecular biological processes, to 
develop mathematical models for quantitating the dynamic process of cell 
differentiation, to identify genes necessary for the successful formation of 
a mature red blood cell and to apply these principles to eukaryotic cells, in 
general.  In the latter stages of erythropoiesis before nuclear extrusion, 
90% of the mRNA transcription results in translation products necessary for 
hemoglobin production.  These studies have led the way for a generalized 
understanding of the transcription process itself.  In addition, the fact 
that each red blood cell must squeeze itself through a narrow capillary 
allows quantitation of biophysical parameters to be made.

The frequency with which red blood cell-related diseases affect humans is a 
public health issue and another focus of this program.  Samples, easily 
obtained from patients, allow performance of multiple tests to monitor 
disease and to develop new therapies for treatment.  In addition, the 
molecular basis of hemoglobinopathies provides a useful teaching and 
education tool.

Objective and Scope
The ultimate goals of this program will be to use erythroid cells at 
different stages of development and differentiation to assemble the complete 
collection of genes expressed, describe how they are expressed and elucidate 
physical parameters, including subcellular localization of the proteins 
translated during erythropoiesis.  These reagents may then be used to 
discover the structure-function relationships that exist in erythroid cells 
with possible application to other cell types.

Appropriate topics for R21 projects would include, but are not limited to the 

o Expansion of cell purification and culture procedures to facilitate rapid 
isolation of morphologically pure stages of erythroid differentiation.

o Characterization of specific classes of proteins in erythroid cells.
o Development of antibodies to specific proteins that may be used as reagents 
for cell biology studies.

o Identification of genes that are expressed during development (i.e., 
embryonic, fetal liver and adult stages) and differentiation (i.e., committed 
CFU-E, pronormoblast, orthochromatophilic erythroblast, polychromatophilic 
erythroblast, and reticulocyte stages) of red blood cells. 

o "Data mining" of molecular genetics to discover functionally important 
biological themes.

o Identification of alternative splicing products and characterization of 
function consequences.

o Testing of novel technologies to evaluate global gene or protein expression.

Appropriate topics for the R01 grant mechanism include, but are not limited 
o Development of molecular genetic descriptions of erythroid cells at various 
stages of development (i.e., embryonic, fetal liver and adult stages) and 
differentiation (i.e., committed CFU-E, pronormoblast, orthochromatophilic 
erythroblast, polychromatophilic erythroblast, and reticulocyte stages and 
red blood cells).  Such global descriptions are needed as standards for the 
entire scientific community.  This includes a determination of which sets of 
genes are expressed at the various stages of erythropoiesis and their 
function in the red blood cell lineages.

o "Data mining" of these above mentioned descriptions to discover functionally 
important biological themes.

o Generation of gene expression profiles that are standardized by use of a 
common set of microarrays, possibly from single cells.  In addition, 
expression profiles need to be developed in cells with specific gene 
knockouts or knockdowns.

o Generation of proteomic profiles.  Some proteins may be present, but not 
active because of post-translational modification.  Included in this may be:  
1) an analysis of the sub-cellular localization of proteins in the erythroid 
proteome, 2) a protein-protein interaction map of the erythroid proteome, and 
3) a comprehensive phenotypic map of loss-of-function of genes encoding the 
erythroid proteome.  Results could be stored as maps, made widely available 
on the Internet.

o Application of molecular knowledge to human diseases.  Among inherited 
disorders of the red blood cell, sickle cell anemia and the thalassemias are 
the most prevalent worldwide.  While the molecular bases of these diseases 
are known, more is needed to learn about the contribution of other genes to 
the clinical course of these illnesses and their overall severity.

o Development of computational biologic programs capable of integrating data 
from all levels of biology, namely DNA, mRNA, protein-protein interactions 
and others.  The goal is to develop mathematical models and graphical 
displays of the red blood cell.

o Comparisons of genomes or sections of genomes that reveal highly conserved 
motifs in erythroid cell development and differentiation.

It is expected that research tools developed will be made readily available 
to the rest of the scientific community.  


This PA will use the NIH R21 or R01 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project.  Applicants are encouraged to contact program staff for 
advice about choosing the appropriate grant mechanism.

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.  Applications requesting $500,000 or 
more in direct costs for any year must follow instructions provided in 
PER YEAR below.  This program does not require cost sharing as defined in the 
current NIH Grants Policy Statement at

R21 (Exploratory/Developmental) grants (see

The R21 mechanism is intended to encourage new exploratory/developmental 
research projects by providing support for the early stages of their 
development.  Awards are made to demonstrate feasibility of a subsequent 
project and to obtain preliminary data testing innovative ideas.  Therefore, 
these grants are not renewable. Continuation of projects developed under this 
program will be through the regular research project grant mechanism (for 
example, R01).  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.  The NIH Grants Policy statement 
applies to these awards.

An R21 application should have a research plan that does not exceed 15 pages.  
A two-year project period is the maximum period of support.  You may request 
a project period of up to two years with a combined budget for direct costs 
up to $275,000 for the two year period.  For example, you may request 
$100,000 in the first year and $175,000 in the second year.  The request 
should be tailored to the needs of your project.  Normally, no more than 
$200,000 may be requested in any single year. Little or no preliminary data 
are required. Up to five relevant published articles may be included as 
Appendix material, if desired.

Exploratory/developmental grant support is for new projects only; competing 
continuation applications will not be accepted.  Two revisions of a 
previously reviewed exploratory/developmental grant application may be 
submitted as defined in NIH Policy at

R01 (Research) grants

The R01 award represents an investigator-initiated research grant designed to 
support a discrete, specified research project performed by a principal 


You may submit an application 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 laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign
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.


Plan for Dissemination of Data and Biomaterials

Sharing of biomaterials, data, and software in a timely manner has been an 
essential element in the rapid progress that has been made in the genetic 
analysis of human diseases.  PHS policy requires that investigators make 
unique research resources available for research purposes to qualified 
individuals within the scientific community when they have been published 
(see the NIH Grants Policy Statement at  In 
addition, NIH recently released a statement on the sharing of research data 
that applies to all investigator-initiated applications with direct costs 
greater than $500,000 in any single year 

All applicants who respond to this PA must propose plans for sharing data and 
biomaterials generated through the grant.  Applicants should explain how 
funds for the storage and distribution of data and biomaterials will be 
obtained, and may request such funds in the budget of the application.  It is 
expected that the information to be shared will include clinical, diagnostic, 
and pedigree structure information.  Biomaterials to be shared should include 
patient DNA and cell lines.  When possible, data and biomaterials should be 
placed in databases or repositories that will permit their efficient 
distribution to investigators throughout the scientific community.  Rapid 
sharing of data and biomaterials is strongly encouraged.

The Initial Review Group will evaluate the proposed sharing plan and comment 
on its adequacy in an administrative note in the summary statement.  
Reviewers will not factor the proposed data-sharing plan into the 
determination of scientific merit or priority score.  NIH staff will consider 
the adequacy of the plan and determine whether the grant shall be awarded.  
The sharing plan as approved, after negotiation with the applicant when 
necessary, will be a condition of the award.


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.
Hematology Genomics Program Director; Training and Careers Program Director
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Blvd., Room 619
Bethesda, MD  20892-5458
Telephone:  (301) 594-7726

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

Donna Huggins
Grants Management Specialist
National Institute of Diabetes, Digestive, and Kidney Diseases
6707 Democracy Blvd., Room 711
Bethesda, MD  20892-5456
Telephone:  (301) 594-8848


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

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

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 includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of the NIH 
institutes or centers who has agreed to accept assignment of the application.

Applicants requesting more than $500,000 must carry out the following steps:

1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and,

3) Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 

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 mailed on or before the receipt 
dates described at  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 application already reviewed, but 
such application must include an Introduction addressing the previous 

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


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 
( will evaluate applications for scientific 
and technical merit.  

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

o Receive a written critique
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 second level review by the appropriate national advisory council 
or board.  


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 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 CRITEIA:  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).
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).

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.  

SPECIFIC R21 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 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


DATA SHARING:  The adequacy of the proposed plan to share data.
BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a 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


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. 

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

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 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 

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.

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). Those who must comply with the Privacy Rule (classified 
under the Rule as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
( 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

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 
PA 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 people.

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