Release Date:  November 26, 2001

RFA:  RFA-DK-02-001

National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  February 15, 2002
Application Receipt Date:       March 15, 2002



The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
and National Institute of Arthritis and Musculoskeletal and Skin Diseases 
(NIAMS) solicit applications for studies designed to apply imaging techniques 
that measure perfusion or tissue oxygenation at the level of the 
microvasculature to the study of diabetes and its complications.  Although 
the etiology of peripheral microvasculature complications in diabetic 
patients is not known, defective perfusion may be an early event.  If so, 
very early detection of changes in perfusion or oxygenation may help to 
identify those patients that are at risk for the microvascular complications 
of diabetes such as neuropathy that can lead to loss of sensation and the 
development of foot ulcers.  Once identified, these patients can be specially 
flagged for intensive treatment in hopes of preventing complications.  The 
ability to image inflammation and angiogenesis in peripheral tissues may help 
to assess wounds and develop optimal treatment plans as well as to monitor 
wound healing in diabetes, and to identify those patients who have 
sufficiently impaired perfusion that they would benefit from 
revascularization procedures.  The ultimate goal of this initiative is to 
provide the diabetes clinical community with reliable, inexpensive tools to 
study the mechanisms leading to the microvascular complications of diabetes 
in peripheral tissues, to detect the early stages of these complications, 
identify patients likely to benefit from therapeutic interventions, and 
monitor disease progression and response to therapy.

A separate RFA, "Surrogate Markers for Diabetic Microvascular Complications", 
DK-02-016 from the National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK), the National Eye Institute (NEI) and the National Institute 
of Neurological Disorders and Stroke (NINDS), invites basic 
and clinical research applications to develop a large range of biochemical, 
cellular, physiologic and genetic surrogate markers that can be used to 
predict risk, aid in early diagnosis and assess progression of all 
microvascular complications of diabetes.


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 Request for 
Applications (RFA), "Imaging Early Markers of Diabetic Microvascular 
Complications in Peripheral Tissue," is related to the priority area of 
diabetes and chronic disabling conditions.  Potential applicants may obtain a 
copy of "Healthy People 2010" at


Applications may be submitted by domestic and foreign for-profit and 
nonprofit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as principal 


This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) and Pilot and Feasibility (R21) award mechanisms. Responsibility 
for the planning, direction, and execution of the proposed project will be 
solely that of the applicant.  The total project period for an application 
submitted in response to this RFA may not exceed 4 years for the R01 and 2 
years for the R21 mechanism.

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

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures.  The anticipated award date is September 30, 2002.


The NIDDK and NIAMS intend to commit approximately $1.0 million in FY 2002 to 
fund 3 to 5 new grants in response to this RFA. Because the nature and scope 
of the research proposed may vary, it is anticipated that the size of each 
award will also vary.  An applicant may request a project period of up to 4 
years using the R01 mechanism. All applications requesting $250,000 direct 
costs per year or less must use the modular budget format.  R21 Pilot and 
Feasibility grant applications should request 2 years at up to $100,000 
direct costs per year.  These applications should propose innovative high 
risk, high yield research, and do not require the extensive preliminary data 
necessary for an R01 application.  Although the financial plans of the NIDDK 
and NIAMS 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 applications of outstanding scientific and technical merit.  At 
this time, it is not known if this RFA will be reissued.



The Diabetes Control and Complications Trial (DCCT) for type 1 diabetes, and 
the United Kingdom Prospective Diabetes Study (UKPDS) for type 2 diabetes 
demonstrated that intensive control of blood glucose levels could 
dramatically reduce the devastating microvascular complications of diabetes.  
The UKPDS also demonstrated a benefit of rigorous blood pressure control in 
preventing microvascular complications.  In the DCCT development of 
complications was reduced both in patients without discernable microvascular 
damage and in those with evidence of early retinopathy at the start of the 
study.  Thus patients identified at an early stage in the development of 
microvascular disease would have a special incentive to maintain good control 
of their blood glucose in an attempt to avoid future health problems.  
Although much work remains to be done to determine the specific events that 
lead to the microvascular complications of diabetes, damage to the 
endothelial cell layer in the vessels themselves by alterations in cytokines, 
nitric oxide, superoxides, advanced glycation endproducts, increased vascular 
endothelial growth factor, etc. may lead to alterations in vessel elasticity, 
leakiness, tissue perfusion and oxygenation.  It may be possible to use 
modern imaging technologies, coupled with exercise or a vasoactive compound 
such as nitric oxide, to identify and localize parameters that correlate with 
an increased risk for developing microvascular diabetic complications.  
Candidate parameters might be blood flow or volume, water diffusion, 
myoglobin or hemoglobin oxygenation, cytochrome oxidation state, or altered 
kinetics of contrast agent extravascularization.  Patients with established 
microvascular disease are at increased risk of foot ulceration that may 
progress and lead to amputation.  It is often difficult to assess the extent 
of a lesion, and patients with what appear to be superficial ulcers may 
benefit from the ability to locate and visualize the extent of inflammation 
to determine the optimal therapeutic approach.  The ability to monitor blood 
flow or angiogenesis may also allow doctors to document early responses to 
therapy for wound healing.  Angiography with contrast agents is associated 
with risks, particularly for patients with diabetic nephropathy.  A non-
invasive method of assessing circulation in the limbs of diabetic patients is 
needed that could identify patients who are good candidates for 
revascularization surgery.  Any of these phenomena may also serve as 
surrogate markers in future clinical trials of prevention or treatment of 
microvascular complications, or may aid basic research to understand the 
pathogenesis of neuropathy.   The ideal technologies would be fairly easy to 
implement, require relatively little training of clinic personnel, and be 
inexpensive or employ already widely distributed medical equipment.

A variety of new spectroscopic and imaging technologies could provide direct 
and indirect measures of blood flow and tissue oxygenation with fine spatial 
resolution.  MRI, optical imaging, and ultrasound can be used to measure 
blood flow and blood volume.  In the brain, blood oxyhemoglobin serves as an 
MRI contrast agent that is sensitive to neural activation.  Other 
measurements of tissue oxygenation have been provided by optical spectroscopy 
of the oxidation states of cytochromes, hemoglobin and myoglobin.  New 
methodologies such as optical tomography make the optical imaging of deep 
tissues possible.  MRI is also used to measure the diffusion of water through 
tissue.  In normal muscle and neural tissue, diffusion is constrained by the 
muscle fibers and nerve sheath.  Disruptions in these structures due to 
ischemia and hypoxia, or due to other types of damage secondary to diabetes 
may be detectable using MRI.  The behavior of injected contrast agents may 
allow the detection of pathological microvessel characteristics such as 
leakiness, loss of patency, or obstruction.

A distinct but similar methodology, molecular imaging, uses contrast agents 
bound to antibodies or other targeting molecules that 'light up' specific 
cell types or sub-organ structures.  By exploiting the unique surface 
molecules expressed in growing vascular tissue and in cells of the immune 
system, molecular imaging has been successfully used to visualize 
angiogenesis and inflammation.  This might be valuable for monitoring wound 
healing, adequacy of debridment, and the extent of tissue involvement in 
patients with diabetic foot disease, a particular interest of NIAMS.

Scope and Objectives

This RFA is intended to support research using animals or human subjects, 
development of equipment to help manage diabetes in the clinic, and limited 
clinical trials to test the utility of potential methodologies for monitoring 
microvascular disease in the diabetic population.  Collaborations between 
scientists with expertise in imaging and those with expertise in diabetic 
complications, or with animal models of diabetes, are encouraged.  
Appropriate topics for investigation under this RFA would include but are not 
limited to:

o Investigation of the relationship between blood flow, tissue perfusion, 
diffusion, oxygenation, non-toxic contrast agent kinetics, etc. in peripheral 
tissues and the development of diabetic microvascular complications;

o Evaluation of imageable parameters in peripheral tissues as markers for 
very early microvascular disease in diabetes;

o Evaluation of imageable parameters as markers of nerve damage in peripheral 

o Application of imaging technology to identify areas of infection, or 
evaluate the extent of infection, in patients with foot ulceration due to 
diabetes.  Emphasis would be on those technologies that could easily be 
translated to the clinic;

o Application of imaging technology to monitor the growth of new blood 
vessels during therapy for injuries such as foot ulcers related to diabetic 
complications, or identify those patients that would benefit from procedures 
to restore circulation;

o Application of imaging technology to enhance understanding of the etiology 
and mechanism of peripheral diabetic microvascular complications;

o Development of new machines (inexpensive, robust, portable) for imaging 
blood flow, oxygenation, etc. for the management of diabetes and its 
complications in the clinic or hospital environment;

o Small clinical trials designed to apply imaging technology to measure 
perfusion, diffusion, oxygenation, angiogenesis, or inflammation and their 
role in complications in the diabetic population.


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 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 


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

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects" that was published in the NIH Guide for 
Grants and Contracts, March 6, 1998, and is available at the following URL 

Investigators may also obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


NIH policy requires education on the protection of human subject participants 
for all investigators submitting NIH proposals for research involving human 
subjects.  This policy announcement is found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:


All applications and proposals for NIH funding must be self-contained within 
specified page limitations. Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites. Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


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:

Applicants may wish to place data collected under this RFA 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.


Prospective applicants are asked to submit, by February 15, 2002, a letter of 
intent that includes a descriptive title of the proposed research; the name, 
address, and telephone number of the Principal Investigator; the identities 
of other key personnel and participating institutions; and the number and 
title of the RFA in response to which the application may be submitted.

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 NIDDK staff to estimate the potential review workload and 
plan the review.

The letter of intent is to be sent to:

Chief, Review Branch 
Division of Extramural Activities, NIDDK
6707 Democracy Boulevard, Rm. 752 MSC 5452
Bethesda, MD  20892-5452
(for express/courier service:  Bethesda, MD  20817)
Telephone:  (301) 594-8897
FAX:  (301) 480-3505


The PHS 398 research grant application instructions and forms (rev. 5/2001) 
at must be used in 
applying for these grants. This version of the PHS 398 is available in an 
interactive, searchable format. The NIH will return applications that are not 
submitted on the 5/2001 version.  For further assistance contact GrantsInfo, 
Telephone 301/710-0267, Email:

All application instructions 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


The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only 
when there is a possibility for an award. It is anticipated that these 
changes will reduce the administrative burden for the applicants, reviewers 
and NIH staff.  The research grant application form PHS 398 (rev. 5/2001) at is to be used in 
applying for these grants, with modular budget instructions provided in 
Section C of the application instructions.  

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:

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 the application receipt date listed in the 
heading of the RFA. If an application is received after that date, it will be 
returned to the applicant without review. Supplemental documents containing 
significant revision or additions will not be accepted, unless applicants are 
notified by the Scientific Review Administrator.  

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.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications previously reviewed, but such applications must 
include an Introduction addressing the previous critique.


Upon receipt, applications will be reviewed for completeness by the CSR and 
responsiveness by the NIDDK and NIAMS.  If the application is not responsive 
to the RFA, NIDDK, NIAMS or CSR staff may contact the applicant to determine 
whether to return the application to the applicant or submit it for review in 
the competition with unsolicited applications at the next review cycle.
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 receive a written 
critique and undergo a process in which only those applications deemed to 
have the highest scientific merit, generally the top half of the applications 
under review, will be discussed, assigned a priority score, and receive a 
second level review by the NIDDK and NIAMS Advisory Councils.

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 discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals.  Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application.  Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score.  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.

(1) 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?

(2) 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?

(3) 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? 

(4) 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)?

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

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  Adequacy of plans to include both genders, minorities and their subgroups, 
and children as appropriate for the scientific goals of the research.  Plans 
for the recruitment and retention of subjects will also be evaluated.

o  The reasonableness of the proposed budget and duration to the proposed 

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

o  Availability of special opportunities for furthering research programs 
through the use of unusual talent resources, populations, or environmental 
conditions in other countries which are not readily available in the United 
States or which provide augmentation of existing U.S. resources.

Letter of Intent Receipt Date:    February 15, 2002
Application Receipt Date:         March 15, 2002
Peer Review Date:                 July 2002
Council Review:                   September 2002
Earliest Anticipated Start Date:  September 30, 2002


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.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Maren R. Laughlin, Ph.D. 
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 6101 MSC 5460
Bethesda, MD  20892-5460
Telephone:  (301) 594-8802
FAX:  (301) 480-3503

Alan N. Moshell, M.D.
Director, Skin Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Building 45, Room 5 AS-25L
45 Center Drive MSC 6500
Bethesda, MD  20892-6500
Telephone:  (301) 594-5017
FAX:  (301) 480-4543

Direct inquiries regarding fiscal matters to:

Denise Payne
Division of Extramural Activities 
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Rm. 733 MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8845 
FAX:  (301) 480-3504

This program is described in the Catalog of Federal Domestic Assistance No. 
93.847 and No. 93.846.  Awards are under authorization of the Public Health 
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 
99-158, 42 USC 241 and 285) and administered under NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is 
not subject to the intergovernmental review requirements of Executive Order 
12372 or Health Systems Agency review.

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

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