PROTEOMICS AND METABOLOMICS IN TYPE 1 DIABETES AND ITS COMPLICATIONS

RELEASE DATE:  October 24, 2003

RFA Number:  RFA-DK-03-024 (see correction NOT-DK-04-001)
 
Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATIONS:
National Institutes of Health (NIH)
 (http://www.nih.gov/)

COMPONENTS OF PARTICIPATING ORGANIZATIONS:  
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
 (http://www.niddk.nih.gov/)
National Institute of Allergy and Infectious Diseases (NIAID) 
 (http://www.niaid.nih.gov)
National Eye Institute (NEI)
 (http://www.nei.nih.gov/) 
National Heart, Lung, and Blood Institute (NHLBI) 
 (http://www.nhlbi.nih.gov/) 
National Institute of Neurological Disorders and Stroke (NINDS) 
 (http://www.ninds.nih.gov/)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.847, 93.867, 98.837, 
93.855, 93.853, 93.865

LETTER OF INTENT RECEIPT DATE:  February 18, 2004
APPLICATION RECEIPT DATE:  March 18, 2004 
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 
National Institute of Allergy and Infectious Diseases (NIAID), National Eye 
Institute (NEI), National Heart, Lung, and Blood Institute (NHLBI), National 
Institute of Neurological Disorders and Stroke (NINDS), and National 
Institute of Child Health and Human Development (NICHD) encourage the 
scientific community to use proteomics technologies to study type 1 diabetes 
(T1D) and its complications.  Proteomic technologies have been successfully 
used for the identification of cancer biomarkers, for the identification of 
novel drug targets and for studying several biological processes relevant to 
human health. High throughput metabolic profiling has been recently 
implemented for metabolomic studies. However, as of today these technologies 
have been applied to study T1D and its complication only in a limited way. 
Moreover, currently available proteomic and metabolomic technologies 
represent a great opportunity for advancing the field of T1D and its 
complications. This RFA intends to promote the use of these technologies to 
study T1D and its complications emphasizing the importance of collaborative 
efforts between investigators with expertise in proteomics or metabolomics 
and investigators with expertise in T1D. 

RESEARCH OBJECTIVES
 
T1D is an autoimmune disease characterized by the destruction of the insulin-
secreting beta cells of the pancreas. Diabetes is difficult to control with 
the current therapies available and as a result patients with T1D may suffer 
devastating long term consequences including accelerated cardiovascular and 
peripheral vascular diseases, nephropathy, retinopathy, neuropathy, oral 
diseases and premature death.  T1D affects an estimated one million Americans 
and the treatment of diabetes and its devastating complications results in 
significant health care expenditures.  

T1D has been extensively described as a chronic disease and the 
identification of several susceptibility loci indicate a genetic component. 
However, in several epidemiologic studies T1DM shows a pattern similar to an 
epidemic disease and migrant studies clearly indicate an environmental 
component.  These studies suggest that if we could identify the environmental 
factors responsible for triggering the disease and develop appropriate 
controls, the large majority of T1DM cases could be prevented.  The 
development of autoimmune diabetes in non-obese diabetic mice also indicate 
the importance of the environmental component and to further emphasize the 
importance of the environmental factors it should be mentioned that 80% of 
the cases of T1D occur in individuals with no apparent family history.  In 
view of these studies it is apparent that characterization of the proteome 
and metabolome at different states of the disease could lead to invaluable 
information for understanding the etiology and development of T1D and its 
complications.

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 questions relevant to T1D and 
its complications. 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. Metabolites are the end 
products of many enzymatic reactions and changes in the metabolic profile of 
biofluids like urine and blood could be index of a particular metabolic state 
or disease. Even though there is no technology available for quantifying and 
identifying all metabolites present in a particular biofluid recent 
developments in mass spectrometry and nuclear magnetic resonance spectroscopy 
make it feasible to do high throughput profiling and quantify large subsets 
of metabolites. The application of metabolomic and proteomic technologies to 
the study of T1D and its complications could further our understanding of the 
etiology and development of this disease.

Islet transplantation has been successfully used for freeing individuals with 
T1D from the need of insulin therapy.  However, this treatment is associated 
with significant side effects, and the long-term risks of the 
immunosuppressive agents used are not known.  Moreover, the protocol requires 
two donor pancreata per recipient; therefore, current levels of organ 
donation provide sufficient organs for only a small fraction of the people 
who could potentially benefit from this therapy.  Thus, there is an imminent 
need of improving the transplantation efficiency and proteomics could be used 
for better characterizing islets preparations.

The complications of T1D account for much of the burden of the disease.  
Emerging information on the molecular mechanisms involved in the pathogenesis 
of complications has identified multiple potential targets for therapeutic 
intervention. The discovery of better targets and the early diagnosis of 
specific complications could allow early treatment preventing its 
development. Proteomics and metabolomics could be used for the analysis of 
biofluids of patients or animal models for identifying biomarkers of 
complications, including cardiovascular diseases, retinopathy, neuropathy and 
nephropathy.
 
This RFA is intended to support innovative research that applies proteomic 
and metabolomic technologies to study T1D and its complications. A multi-
disciplinary team composed of a basic or clinical scientist with expertise in 
T1D and a scientist with expertise in proteomics or metabolomics is 
envisioned as the ideal team for approaching most of the projects with 
relevance to this RFA.

To foster the formation of these multidisciplinary teams a conference on 
Proteomics and Diabetes was held 
(http://www.niddk.nih.gov/fund/other/proteomics/index.htm). Furthermore, the 
following web sites contain information about several investigators, 
resources and consortia already working in the field of T1D that might be 
interested in collaborative projects 
(http://www.niddk.nih.gov/fund/diabetesspecialfunds/proteomics/; 
http://www.niddk.nih.gov/researchprograms/resources.htm; 
http://www.niddk.nih.gov/patient/patient.htm). 

Examples of projects that this RFA intends to solicit include but are not 
limited to:

o Identification of surrogate markers for the progression of T1D and the 
development of complications in humans and animal models that develop 
autoimmune diabetes and/or the complications of diabetes

o Application of proteomic technologies to study the inflammatory processes 
leading to the development of T1D and its complications

o Application of proteomics and metabolomics to assess the risk of developing 
T1D or monitor response to therapy to prevent or reverse the autoimmune 
process

o Application of proteomic technologies for identifying novel drug targets 
for the treatment and prevention of T1D and its complications, and for 
monitoring the efficacy of present treatments

o The use of proteomic approaches for identifying markers for monitoring 
pancreatic beta cell differentiation, development, function, and/or mass

o The characterization of the pancreatic islet proteome for identifying 
markers that might be used for improving the success rate in transplantation

o The development of antibodies or protein/antibody arrays that could be used 
for studying T1D or screening islets to be transplanted and/or monitor their 
function after transplantation that can be used for screening islets to be 
transplanted and/or monitor their function after transplantation

MECHANISMS OF SUPPORT

This RFA will use the NIH Exploratory/Development Research Grant (R21), the 
Exploratory/Development Research Grant Phase 2 (R33), and the Phased 
Innovation Award (R21/R33 combined).  The R33 is an NIH grant mechanism to 
provide a second phase for the support of innovative exploratory and 
development research initiated under the R21 mechanism.  Under the Phased 
Innovation Award (R21/R33), transition of the R21 to the R33 phase will be 
expedited and is dependent on completion of negotiated milestones.  As an 
applicant you will be solely responsible for planning, directing, and 
executing the proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project will 
have to be submitted using a standard RO1 or R21 mechanism, will compete with 
all investigator-initiated applications and will be reviewed according to the 
customary peer review procedures. The anticipated award date is September 30, 
2004. Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using the 
standard receipt dates for NEW applications described in the instructions to 
the PHS 398 application.  

This RFA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
https://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 format.  Otherwise follow the instructions for non-
modular research grant applications.  This program does not require cost 
sharing as defined in the current NIH Grants Policy Statement at 
https://grants.nih.gov/archive/grants/policy/nihgps_2001/part_i_1.htm.  

Specific features of the Phased Innovation Award Mechanism (R21/33 Combined) 
include: 

o Single submission and evaluation of both a feasibility/pilot phase (R21) 
and an expanded development phase (R33) as one application. 
o Expedited transition of the R21 feasibility phase to an R33 development 
phase.
o Flexible budgets.
o Flexible staging of feasibility and development phases.

The use of the multiple mechanisms will allow projects to be submitted at 
various stages of development.  The R21 will provide support for projects in 
early stages of development where there is little or no preliminary data 
available and it is difficult to predict success sufficiently to develop an 
extended R33 phase.  The R33 will provide support for projects in which 
feasibility has been demonstrated and thus are ready for extended 
development. The combined R21/R33 will provide support for projects that 
require feasibility demonstration, and the aims and milestones of the R21 are 
sufficiently predictable to consider the extended R33 phase.

Responsibility for the planning, direction and execution of the proposed 
research project will be solely that of the applicant.  Except as otherwise 
stated in this RFA, awards will be administered under the NIH grants policy 
as stated in the NIH Grants Policy Statement, March 2001, available from the 
internet only at https://grants.nih.gov/grants/policy/nihgps_2001/.

Under this RFA, applicants may submit either an R21 application, a combined 
R21/R33 application (Phased Innovation Award application) or the R33 
application alone, if feasibility can be documented, as described in the 
SUBMITTING AN APPLICATION section of this RFA.  The total project period for 
an application in response to this RFA may not exceed the following 
durations: 2 years for the R21 phase; 3 years for the R33 phase; 5 years for 
a combined R21/R33 proposal. In the combined application, the R21 phase may 
not extend beyond 2 years.  

The combined R21/R33 application offers two advantages over the regular 
application process:

1.  Single submission and evaluation of both the R21 and the R33 phases as 
one application.

2.  Minimal or no funding gap between the R21 and R33.  The award of the R33 
funds will be based on program priorities, the availability of funds and the 
successful completion of negotiated scientific milestones as determined by 
program staff in the context of peer review recommendations.

To be eligible for the Phased Innovation Award, the R21 phase must include 
well-defined quantifiable milestones that will be used to judge the progress 
and success of the proposed research, as well as a credible plan for the R33 
phase.  The Phased Innovation Award must have a section labeled Milestones at 
the end of the Research Plan of the R21 application.  This section must 
include well-defined quantifiable milestones for the completion of the R21 
portion of the application, a discussion of the suitability of the proposed 
milestones for assessing the success in the R21 phase, and a discussion of 
the implications of successful completion of the milestones for the proposed 
R33 study.

FUNDS AVAILABLE
 
The participating ICs intend to commit approximately $3 million in FY 2004 to 
fund 6 to 12 new grants in response to this RFA.  An applicant may request a 
project period of 2 (R21 phase alone), 3 (R33 phase alone) or 5 (R21/R33 
combined) years.  For R21 and combined R21/R33 applications, the R21 phase 
may not exceed $250,000 direct costs per year.  R21 budgets can exceed this 
cap to accommodate F&A costs to subcontracts to the project, in which case a 
non-modular budget format must be used.  The R33 application has a budgetary 
limit of $500,000 direct costs for each year.

Because the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and duration of 
each award will also vary. Although the financial plans of the IC(s) provide 
support for this program, awards pursuant to this RFA are contingent upon the 
availability of funds and the receipt of a sufficient number of meritorious 
applications. 
 
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 Units of State and local governments
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. 

SPECIAL REQUIREMENTS 

Applicants from institutions which have a General Clinical Research Center 
(GCRC) funded by the NIH National Center for Research Resources may wish to 
identify the GCRC as a resource for conducting the proposed research. In such 
a case, a letter of agreement from either the GCRC program director or 
principal investigator should be included with the application.  
 
WHERE TO SEND INQUIRIES

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

o Direct your questions about scientific/research issues to:

Salvatore Sechi, Ph.D.
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
E-mail: ss24q@nih.gov

John Paul Ridge, Ph.D.
Division of Allergy, Immunology, and Transplantation 
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Drive, Rm. 5259 
Bethesda, MD  20892-7640 
Telephone:  (301) 496-7104 
FAX:  (301) 402-2571 
E-mail: jr34g@nih.gov

Peter A. Dudley, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  (301) 402-0528
E-mail:  pd8n@nih.gov 

Pothur Srinivas, Ph.D., MPH
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Rm. 10188
6701 Rockledge Drive
Bethesda, MD 20892-7956
Phone: (301) 435-0550
FAX: (301) 480-2858
E-mail: ps241q@nih.gov 
 
Paul L. Nichols, Ph.D. 
Systems and Cognitive Neuroscience
National Institute of Neurological Disorders and Stroke 
Neuroscience Center, Rm. 2108 
6001 Executive Blvd. 
Bethesda, MD 20892 
Phone: (301) 496-9964 
FAX: (301) 401-2060 
E-mail: pn13w@nih.gov

Gilman D. Grave, M.D.  
Center for Research for Mothers and Children  
National Institute of Child Health and Human Development  
6100 Executive Boulevard; Suite 4B-11  
National Institutes of Health  
Bethesda, MD 20892-7510  
Telephone: (301) 496-5593  
Fax: (301) 480-9791  
E-mail address: gg37v@nih.gov  

o Direct your questions about peer review issues to:

Francisco O. Calvo, Ph.D.
Division of Extramural Activities,
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505
E-mail: fc15y@nih.gov 

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

Ms. Denise Payne
Grants Management Branch
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
E-mail: dp43b@nih.gov 

Chris Davis
Grants Management 
National Eye Institute
6120 Executive Blvd, Suite 350
Bethesda, MD  20892-7164
Telephone:  (301) 451-2020
FAX:  (301) 496-9997
E-mail:  cd224z@nih.gov 

Norma DeGuzman
Grants Operation Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Rm. 7167
Bethesda, MD 20892-7926
Telephone:  (301) 496-6740
Fax: (301) 480-1948
E-mail:    nd76f@nih.gov
 
Karen Shields
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Rm. 3290
6001 Executive Blvd.
Bethesda, MD 20892
Phone: (301) 496-9231
FAX: (301) 402-0129
E-mail: ks26n@nih.gov

Gilman D. Grave, M.D.  
Center for Research for Mothers and Children  
National Institute of Child Health and Human Development  
6100 Executive Boulevard; Suite 4B-11  
National Institutes of Health  
Bethesda, MD 20892-7510  
Telephone: (301) 496-5593  
Fax: (301) 480-9791  
E-mail address: gg37v@nih.gov   

LETTER OF INTENT
 
Prospective applicants are asked to submit a letter of intent that includes 
the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

Although a letter of intent is not required, is not binding, and does not 
enter into the review of a subsequent application, the information that it 
contains allows IC staff to estimate the potential review workload and plan 
the review.
 
The letter of intent is to be sent by the date listed at the beginning of 
this document.  The letter of intent should be sent to:

Chief, Review Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

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

I. SPECIFIC INSTRUCTIONS FOR PREPARING THE COMBINED R21/R33 PHASED INNOVATION 
AWARD APPLICATION:

The R21/R33 application must include the specific aims for each phase and 
clear measurable goals (milestones) that would demonstrate feasibility and 
justify transition to the R33 phase.  Applications must include a specific 
section labeled Milestones following the Research Plan of the R21 phase.  
Milestones should be well described, quantifiable and scientifically 
justified and not simply a restatement of the specific aims. A discussion of 
the milestones relative to the progress of the R21 phase, as well as, the 
implications of successful completion of the milestones for the R33 phase 
should be included. 

This section should be indicated in the Table of Contents.  Applications 
lacking this information, as determined by the NIH program staff, will be 
returned to the applicant without review.  For funded applications, 
completion of the R21 milestones will elicit an NIH expedited review that 
will determine whether or not the R33 should be awarded. The release of R33 
funds will be based on successful completion of negotiated scientific 
milestones, program priorities, and on the availability of funds. The 
expedited review may result in additional negotiations of award.

The R21/R33 combined applications must be submitted as a single application, 
with one face page.  Although it is submitted as a single application, it 
should be clearly organized into two phases.  To accomplish a clear 
distinction between the two phases, applicants are directed to complete 
Sections a-d of the Research Plan twice: one write-up of Sections a-d and 
milestones for the R21 phase and sections a-d again for the R33 phase.  The 
Form 398 Table of Contents should be modified to show sections a-d for each 
phase as well as the milestones.  There is a page limit of 25 pages for the 
composite a-d text of all applications (i.e., section a-d and milestones for 
the R21 phase plus sections a-d for the R33 phase must be contained within 
the 25 page limit for R21/R33 applications.)

In preparing the R21/R33 application, investigators should consider the fact 
that applications will be assigned a single priority score.  In addition, as 
discussed in the REVIEW CONSIDERATIONS section, the initial review panel has 
the option of recommending only the R21 phase for support.  However, an 
application with an R33 Phase that is so deficient in merit that it is not 
recommended for support will reflect upon the judgment of the applicant.  For 
these reasons, the clarity and completeness of the R21/R33 application with 
regard to specific goals and feasibility milestones for each phase are 
critical. The presentation of milestones that are not sufficiently 
scientifically rigorous to be valid for assessing progress in the R21 phase 
will reflect upon the scientific judgment of the applicant in this 
application.

1.  Face Page of the application:
Item 2.  Check the box marked "YES" and type the number and title of this 
RFA.  Also indicate that the application is submitted as an R21/R33.

Item 7a, DIRECT COSTS REQUESTED FOR INITIAL PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs are 
limited to a maximum of $250,000 per year for a maximum of two years and the 
award may not be used to supplement an ongoing project.  The requested 
budgets can exceed this cap to accommodate for F&A costs to subcontracts to 
the project.  Insert the first year of R21 support in item 7a.

Item 8a, DIRECT COSTS REQUESTED FOR PROPOSED PERIOD OF SUPPORT:
For the R21 phase of the combined R21/R33 application, direct costs requested 
for the proposed period may not exceed $500,000 for two years of support.  
The statement in item 7a above pertaining to subcontract costs also applies 
here. Insert sum of all years of requested support in item 8a.

2.  Page 2 - Description:
As part of the description, identify concisely the research team, the 
fundamental research to be performed or the 
technology/tool to be developed, its innovative nature, its relationship to 
presently available knowledge or capabilities, and its expected impact on the 
diagnosis, treatment or prevention of type 1 diabetes or its complications.

3. Budget:
The application should provide a DETAILED BUDGET for Initial Budget Period 
(form page 4), for each of the initial years of the R21 and R33 phases as 
well as a budget for the entire proposed period of support (form page 5).  
Form pages should indicate which years are R21 and R33.  All budgets should 
include a justification for each item requested.

4.  Research Plan:
Item a, Specific Aims: The applicants must present specific aims that the 
applicant considers to be scientifically appropriate for the relevant phases 
of the project.  The instructions in the PHS 398 booklet for this section of 
research grant applications suggest that the applicant state the hypotheses 
to be tested.  Furthermore for the R21 phase, preliminary data are not 
required, although they should be included when available. 

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in 
this project will result in a significant improvement over existing 
approaches.  Explain the potential of the proposed studies for having a broad 
impact on a compelling area of type 1 diabetes research. Clearly identify how 
the project, if successful, would result in new capabilities for the 
treatment and prevention of type 1 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
While preliminary data are not required for the submission of the R21 phase, 
this section should provide current thinking or evidence in the field to 
substantiate the feasibility of the R33 phase.  While preliminary data are 
not required for submission of the R21 phase, easily understandable data that 
provide relevant information to aid the review should be included when 
available. The R33 phase need not repeat information already provided in the 
R21 phase.

Item d, Research Design and Methods:
Follow the instructions in the PHS 398 booklet.  In addition, for the R21 
phase of combined R21/R33 applications only, the following information must 
be included as a final section of Item d:

Applications must include a specific section labeled Milestones following the 
Research Design and Methods of the R21 phase.  Milestones should be well 
described, quantifiable, and scientifically justified and not be simply a 
restatement of the specific aims. The milestones should not be a reiteration 
of the Specific Aims of the research project, but should be tangible 
accomplishments.  A discussion of the milestones relative to the success of 
the R21 phase, as well as the implications of successful completion of the 
milestones for the R33 phase and the page number of the milestones section 
should be listed. This section should be indicated in the Table of Contents. 

Applications lacking this information, as determined by the Institute program 
staff, will be returned to the applicant without review.  For funded 
applications, completion of the R21 milestones will elicit an Institute 
expedited review that will determine whether or not the R33 should be 
awarded. The release of R33 funds will be based on successful completion of 
milestones, program priorities and on the availability of funds. The 
expedited review may result in additional negotiations of award.

II. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R21 APPLICATION WHEN 
SUBMITTED WITHOUT THE R33 PHASE.

MODULAR GRANT APPLICATION:
R21 only applications should be submitted in a modular grant format, unless 
exceeding the $250,000 budgetary cap in order to accommodate F&A costs to 
subcontracts to the project.  The total project period for an R21 application 
may not exceed two years.  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 https://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 
https://grants.nih.gov/grants/funding/modular/modular.htm.

1.  Face page of the application: 
Item 2. Check the box marked "YES" and type the number of this RFA.  Also 
indicate that the application is for an R21.

2.  Page 2, Description:
As part of the description, identify concisely the research team, the 
fundamental research to be performed or the technology/tool to be developed, 
its innovative nature, its relationship to presently available knowledge or 
capabilities, and its expected impact on the diagnosis, treatment or 
prevention of type 1 diabetes or its complications.

3.  Research Plan:
Item a, Specific Aims: The applicants must present specific aims that the 
applicant considers to be scientifically appropriate for the relevant phases 
of the project.  The instructions in the PHS 398 booklet for this section of 
research grant applications suggest that the applicant state the hypotheses 
to be tested.  Furthermore for the R21 phase, preliminary data are not 
required, although they should be included when available.

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in 
this project will result in a significant improvement over existing 
approaches.  Explain the potential of the proposed studies for having a broad 
impact on a compelling area of type 1 diabetes research. Clearly identify how 
the project, if successful, would result in new capabilities for the 
treatment and prevention of type 1 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
R21 applications should provide current thinking or evidence in the field to 
support the project.  While preliminary data are not required, easily 
understandable data that provide relevant information to aid review could be 
included when available.

Item d, Research Design and Methods:
Instructions for PHS 398 should be followed.

III. SPECIFIC INSTRUCTIONS FOR PREPARATION OF THE R33 APPLICATION WHEN 
SUBMITTED WITHOUT THE R21 PHASE.

Applications for R33 grants are to be prepared according to the instructions 
provided in the PHS 398 booklet unless specified otherwise within items 1-4 
below.  

1.  Face Page of the application:
Item 2. Check the box marked "YES" and type the number and title of this RFA.  
Also, indicate that the application is for an R33.

2.  Page 2 - Description:
As part of the description, identify concisely the research team, the 
fundamental research to be performed or the technology/tool to be developed, 
its innovative nature, its relationship to presently available knowledge or 
capabilities, and its expected impact on the diagnosis, treatment or 
prevention of type 1 diabetes or its complications.

3.  Budget:  
The application should provide a DETAILED BUDGET for the Initial Budget 
Period (form page 4) as well as a budget for the entire proposed period of 
support (form page 5).  Budget should include a justification of all items 
requested.

4.  Research Plan:

Item a, Specific Aims:

The instructions in the PHS 398 booklet for this section of research grant 
applications suggest that the applicant state the hypotheses to be tested. 

Item b, Background and Significance:
Elaborate on the innovative nature of the proposed research. Clarify how the 
fundamental research or tools/technologies to be developed as proposed in 
this project will result in a significant improvement over existing 
approaches.  Explain the potential of the proposed studies for having a broad 
impact on a compelling area of type 1 diabetes research. Clearly identify how 
the project, if successful, would result in new capabilities for the 
treatment and prevention of type 1 diabetes and its complications.

Item c, Preliminary Studies/Progress Report:
This section must document that feasibility studies have been completed, and 
progress achieved, equivalent to that expected through the support of an R21 
project.  The application must clearly describe how the 
exploratory/developmental study is ready to scale up to an expanded 
development stage.  In the event that an applicant feels that some aspect of 
the approach or tools or technology to be developed is too proprietary to 
disclose, applicants at a minimum should provide a demonstration (results) of 
the capabilities of the proposed approach, tool or technology.

Item d, Research Design and Methods:
Follow the instructions in the PHS 398 booklet. 

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) 
application form must be affixed to the bottom of the face page of the 
application.  Type the RFA number on the label.  Failure to use this label 
could result in delayed processing of the application such that it may not 
reach the review committee in time for review.  In addition, the RFA title 
and number must be typed on line 2 of the face page of the application form 
and the YES box must be marked. The RFA label is also available at: 
https://grants.nih.gov/grants/funding/phs398/labels.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the Checklist, and three signed, photocopies, in 
one package to:
 
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)
 
At the time of submission, two additional copies of the application and all 
copies of the appendix material must be sent to:

Chief, Review Branch 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 752
Bethesda, MD  20892-5452
(for express/courier service: Bethesda, MD  20817)
 
APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the applicant 
without review. 

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.
 
The Center for Scientific Review (CSR) will not accept any application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  
However, when a previously unfunded application, originally submitted as an 
investigator-initiated application, is to be submitted in response to an RFA, 
it is to be prepared as a NEW application.  That is, the application for the 
RFA must not include an Introduction describing the changes and improvements 
made, and the text must not be marked to indicate the changes from the 
previous unfunded version of the application.  

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK.  Incomplete and/or nonresponsive applications 
will not be reviewed. Do not accept unsolicited R21/R33 applications.  
Applications that are complete and responsive to the RFA will be evaluated 
for scientific and technical merit by an appropriate peer review group 
convened by the NIDDK in accordance with the review criteria stated below.  
As part of the initial merit review, all applications will:

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

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate the application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application's overall score, weighting them as appropriate for each 
application. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment

The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 
forward.

SIGNIFICANCE: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced? What 
will be the effect of these studies on the concepts or methods that drive 
this field?  Is the research partnership likely to contribute to new and 
important discoveries about type 1 diabetes?

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: Are 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:

For an R21/R33 application, the initial review group will evaluate the 
specific goals for each phase and the feasibility of the milestones that 
would justify expansion to the R33 phase.  The initial review group will 
evaluate how appropriate, realistic and quantifiable your proposed research 
milestones are, and whether the milestones are adequate for the demonstration 
and feasibility for transition to the R33 development phase.  They will also 
assess your timeframe for achieving the milestones and whether it is 
appropriate.  A single priority score will be assigned to each scored 
application.  As with any grant application, the initial review group has the 
option of recommending support for a shorter duration than that requested by 
the applicant, and basing the final merit rating on the recommended portion 
of the application.  For the R21/R33 application, this may result in a 
recommendation that only the R21 phase be supported, based upon concerns 
related to the application's specific goals and the feasibility milestones 
justifying expansion to the R33 phase.  Deletion of the R33 phase by the 
review panel or presentation of inadequate milestones in the application may 
affect the merit rating of the application.

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.  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.

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:          February 1, 2004
Application Receipt Date:               March 1, 2004
Peer Review Date:                       June/July 2004
Council Review:                         September 2004
Earliest Anticipated Start Date:        September 30, 2004

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
 
REQUIRED FEDERAL CITATIONS 

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.  
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN:  Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II); efficacy, 
effectiveness and comparative trials (phase III).  The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants. (NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
https://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

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

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). 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 
(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 
https://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 
RFA 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 
https://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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