RELEASE DATE:  January 7, 2003

PA NUMBER:  PA-03-052

EXPIRATION DATE:  After 02/01/2006, unless reissued. 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Cancer Institute (NCI)


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Information about a Workshop on Proteomics
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


This program announcement is part of a larger NIDDK and NCI proteome 
initiative and seeks to promote the use of proteomic technologies for 
studying diabetes and its complications, and other endocrine and metabolic 
diseases. The development and improvement of innovative proteomic 
technologies is also encouraged through their application to relevant 
biological questions related to diabetes, endocrinology and metabolic 



High throughput DNA sequencing has changed biomedical research. The complete 
sequence of the genome for 100 organisms and the nearly complete sequence of 
many others, including the human, are giving a new vision to the study of 
biological systems. It is, however, apparent that knowledge of the genome 
alone is not sufficient for a complete understanding of complex biological 
processes. While the genome is the same in different cell types within an 
organism and does not change with time, the proteome varies with time and 
among different cell types. The gene function is usually fulfilled through 
its protein whereas its potential is indicated by the genome. In view of 
recent large-scale data showing that often there is a poor correlation 
between mRNA quantities and protein quantities, we cannot limit gene 
expression studies to the RNA level but must also investigate biological 
problems at the protein level. Despite the significant limitations of using 
mRNA arrays for studying gene expression, relatively few investigators have 
used proteomic approaches. Moreover, post-translational modifications, 
regulation of protein function by proteolysis, and composition of 
macromolecular complexes or organelles can only be determined at the protein 
level, further emphasizing the importance of studying the proteome. 

Proteomic approaches have been successfully used for studying complex 
biological problems and for the identification of disease markers. Recent 
developments in proteomics indicate that the technologies available are 
already sufficiently advanced to approach many biological questions relevant 
to the NIDDK mandate. Some of these technologies include: two-dimensional gel 
electrophoresis for profiling complex mixtures coupled to mass spectrometry 
or other methods for protein identification; isotopically labeled reagents 
for the comparison of two different biological states (e.g. disease versus 
control) using mass spectrometry; protein or antibody arrays; yeast two-
hybrid systems, phage display or immunoprecipitation coupled to mass 
spectrometry for studying protein-protein interactions; characterization of 
macromolecular complexes using antibodies, DNA, RNA, or other molecules as 
bait followed by identification by mass spectrometry; and computational 
methods for structure/function prediction.  None of the above technologies is 
capable of analyzing the whole proteome at once. However, the study of a 
subset of the proteome is feasible, and could be applied to a specific 
biological system and/or disease of interest.  

There is also a need to further improve the present technologies and develop 
novel approaches for studying the proteome that are more sensitive and more 
comprehensive. These technology developments would be of particular interest 
when accomplished through projects directed at understanding or solving 
problems related to organs and/or diseases of interest to the NIDDK

Examples of projects that the NIDDK and NCI is soliciting through this PA 
include but are not limited to:

o Identification of surrogate markers looking at the plasma/serum proteome at 
different stages of development of diabetes, its complications or other 
endocrine or metabolic diseases. 

o Use of proteomic approaches to study the signal transduction network of the 
insulin receptor and/or other cell surface receptors (e.g. G-protein coupled 
receptors (GPCR), Ser/Thr kinase receptors, growth factor receptors, and 
cytokine receptors) relevant to diabetes, its complications, or other 
endocrine or metabolic diseases.

o Characterization of the proteome or a subset of the proteome of animal and 
cell models relevant to diabetes, its complications, or other endocrine or 
metabolic diseases.  

o Use of proteomic approaches for studying carbohydrate, lipid and protein 
metabolism, hormonal control of metabolism and its alteration in diabetes and 
other endocrine or metabolic diseases.

o Identification of novel signaling molecules and pathways involved in cell 
development, differentiation, communication, function and destruction, as 
applied to diabetes, endocrinology, and metabolic diseases.

o Use of proteomic approaches for studying the regulation, synthesis, 
secretion, and action of hormones and cytokines relevant to diabetes, its 
complications, and endocrinology and metabolic diseases. 

o Use of proteomic approaches for the characterization of macromolecular 
complexes relevant to diabetes, its complications, or other endocrine or 
metabolic diseases.

o Use of proteomic approaches to study nuclear receptors (e.g. steroid and 
thyroid hormone and orphan nuclear receptors) and their action, including the 
roles of receptors and/or nuclear accessory proteins, including coactivators, 
corepressors, and chromatin remodeling protein complexes. 

o Use of proteomics to characterize the signal transduction networks of one 
or more specific receptor system(s) to determine mechanisms underlying 
specificity of response integration of signaling systems, and coupling 
hormone signaling to changes in gene expression.

o Use of proteomic approaches for identifying surface markers for monitoring 
pancreatic beta cell differentiation, development, function, and/or mass. 

o Development and/or use of computational proteomics tools to analyze and/or 
annotate the genome as it might apply to information relevant to diabetes, 
its complications, or other endocrine or metabolic diseases.

o Development and/or use of bioinformatics tools to study the proteome as it 
might apply to information relevant to diabetes, its complications, or other 
endocrine or metabolic diseases.

o Identification of novel drug targets or novel therapeutic agents using 
proteomic approaches that might be relevant to diabetes, its complications, 
or other endocrine or metabolic diseases.

o Characterization of the proteome or a subset of the proteome for toxicology 
studies of drugs that might be relevant to diabetes, its complications, or 
other endocrine or metabolic diseases.

o Characterization of the effect on the proteome or a subset of the proteome 
of drugs/agents that are currently used to treat or prevent diabetes, its 
complications, or other endocrine or metabolic diseases.

The above examples are not meant to be comprehensive or to restrict ideas to 
these particular concerns. However, they do represent some of the projects 
that would be relevant to the NIDDK and NCI mission.


This PA will use the NIH R01 and R21 award mechanisms.  As an applicant, you 
will be solely responsible for planning, directing, and executing the 
proposed project. For the R21 there is a limit of 2 years at $100,000/year in 
requested support.  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 standard instructions 
in the PHS 398 form.


The NIDDK recently announced that it will decrease the use of one-time 
solicitations, (e.g. the request for application (RFA) mechanism) and 
substitute use of special emphasis funding for selected program announcements 
(PA) to stimulate research in areas of particular importance.  Applications 
responsive to these Special Emphasis PAs will receive automatic consideration 
for funding beyond the regular grant payline.   The NIDDK is strongly 
committed to the use of proteomic technologies to advance research in 
diabetes, endocrinology and metabolic diseases, and has selected this PA to 
be a Special Emphasis PA.  Further information about NIDDK Special Emphasis 
PAs can be found at

Funding will also be dependent on the receipt of applications of high 
scientific merit and on the availability of funds for this purpose.  This PA 
will remain active through the February 1, 2006 receipt date, after which 
applications submitted within the scientific scope of this PA will compete 
without the special emphasis benefit.


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

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


This PA is one component of a multi-faceted initiative to foster application 
of proteomic technologies to diabetes, its complications, and other endocrine 
and metabolic diseases.  Another component of the proteome initiative is the 
workshop Proteomics in Diabetes that will occur in Bethesda on April 23-25, 
2003 ( Importantly 
this workshop will provide a venue to bring together investigators with 
expertise in proteomics and those interested in applying this technology to a 
problem related to diabetes, endocrinology and metabolic diseases.  Important 
goals of the workshop will be exchange of information as well as fostering 
new research collaborations among participants. All prospective applicants 
are invited to attend. NIDDK and NCI staff will be available to answer any 
questions about the solicitation.  In addition, the workshop will facilitate 
identification of potential research partners and initiation of collaborative 
efforts, which may be important for development of a successful application. 
The NIDDK anticipates participants in this workshop will be drawn from 
multiple disciplines spanning the technology and biology fields.


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 encouraged to 


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:

Salvatore Sechi, Ph.D.
Director, Proteomic Program
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd. Rm. 611
Bethesda, MD 20892-5460
Telephone: 301-594-8814
FAX: 301-480-2688

Mukesh Verma, Ph.D.
Division of Cancer Prevention
National Cancer Institute
6130 Executive Blvd., Rm. EPN 3144
Rockville, MD  20852-7362
Telephone: 301-496-3893
FAX: 301-402-8990

o Direct your questions about financial or grants management matters relevant 

Ms. Denise Payne
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Rm.733
Bethesda, MD 20892-5460
Telephone: 301-594-8845
FAX: 301-480-3504

Mr. Brian E. Martin
Grants Management Specialist
National Cancer Institute
6120 Executive Blvd., Rm. EPS 243
Bethesda, MD  20892-7148
Telephone: 301-846-7148
FAX: 301-846-5720


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, and include 
February 1, June 1, and October 1.  These application deadlines are also 
indicated in the PHS 398 application kit.

outlined in the PHS 398 application kit are to be followed, with the 
following requirements 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

requesting up to $250,000 per year in direct costs must be submitted in a 
modular grant format.  The modular grant format simplifies the preparation of 
the budget in these applications by limiting the level of budgetary detail.  
Applicants request direct costs in $25,000 modules.  Section C of the 
research grant application instructions for the PHS 398 (rev. 5/2001) at 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 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;  
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)

Applications must be received by or 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 


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 National Diabetes and Digestive and 
Kidney Diseases Advisory Council or the National Cancer Advisory 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 your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

SIGNIFICANCE:  Does your study address an important problem? If the aims of 
your application are achieved, how do they advance scientific knowledge? What 
will be the effect of these studies on the concepts or methods that drive 
this field?

APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 

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

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

ENVIRONMENT:  Does the scientific environment in which your work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?

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

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans 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 included in the 
section on Federal Citations, below)

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


involving Phase I and II clinical trials must include provisions for 
assessment of patient eligibility and status, rigorous data management, 
quality assurance, and auditing procedures.  In addition, it is NIH policy 
that all clinical trials require data and safety monitoring, with the method 
and degree of monitoring being commensurate with the risks (NIH 
Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, 
June 12, 1998:  

the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the AMENDMENT "NIH 
Guidelines for Inclusion of Women and Minorities as Subjects in Clinical 
Research - Amended, October, 2001," published in the NIH Guide for Grants and 
Contracts on October 9, 2001
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 

The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 

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.

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 No. 93.847 (NIDDK) and 93.393 (NCI) and is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review. Awards are made under authorization of 
Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284) and administered under NIH grants policies described at under Federal Regulations 42 
CFR 52 and 45 CFR Parts 74 and 92.

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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