Release Date:  May 10, 2001

RFA:  RFA-DK-01-028

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  October 15, 2001
Application Receipt Date:       November 13, 2001


Cystic Fibrosis (CF) Research Centers foster multi-disciplinary 
approaches to research ranging from elucidation of the molecular 
pathogenesis of CF to development of new therapies for this disorder.  
It is anticipated that one award will be made in response to this 
Request for Applications (RFA) in FY 2002.  The receipt of one 
competing continuation application is anticipated, and this application 
will be in competition together with other applications
received in response to this RFA.


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), Cystic Fibrosis Research Centers, is related to the 
priority area of chronic diseases.  Potential applicants may obtain a 
copy of "Healthy People 2010" at


Applications may be submitted by domestic 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 investigators.


This RFA will use the National Institutes of Health (NIH) Specialized 
Center of Research (SCOR) grant (P50) award mechanism. Supplemental 
guidelines for preparing a SCOR application are available from Staff 
listed under Inquiries.  Responsibility for the planning, direction, 
and execution of the proposed project will be solely that of the 

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 

This RFA is a one-time solicitation.  The NIDDK only accepts new and 
competing continuation SCOR applications in response to an RFA. The 
total project period for an application submitted in response to this 
RFA may not exceed 5 years. The maximum dollar request is limited to 
$750,000 in direct costs for each budget period. The anticipated award 
date is September 1, 2002.


The NIDDK intends to commit approximately $1,000,000 total costs in FY 
2002 to fund 1 new or competing continuation grant in response to this 
RFA. An applicant may request a project period of up to 5 years and a 
budget for direct costs of up to $750,000 per year, excluding indirect 
costs on consortium arrangements.  Because the nature and scope of the 
research proposed may vary, it is anticipated that the size of each 
award will also vary. Although the financial plans of the NIDDK 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.


Cystic Fibrosis is a genetic disease affecting approximately 30,000 
persons in the U.S.  This disease, which is present from birth, has had 
improved survival due to better management of the infections and 
nutritional aspects of the disorder.  With the identification of the 
genetic cause of CF as mutations in the cystic fibrosis transmembrane 
conductance regulator (CFTR), many studies have been undertaken to 
identify the functions of this protein and to determine the 
pathophysiology of the disease.  It is clear that CFTR interacts with 
many other proteins including accessory proteins, scaffolding proteins 
and other ion channels to carry out its cellular function. Based on our 
current understanding of the functions and interactions of CFTR, new 
therapeutic interventions are being evaluated for both their efficacy 
and their safety.  The interactions of researchers from many different 
backgrounds will be required to translate our understanding of the 
complex actions of CFTR into therapies for cystic fibrosis.

Specialized Centers of Research (SCORs) support broadly-based multi-
disciplinary or multifaceted research programs pursuing a range of 
scientific questions with a central research focus.  Each SCOR must 
have a clearly defined, unifying central theme to which each project 
relates and to which each investigator contributes.  This theme must 
address the central questions relevant to elucidation of the 
pathogenesis of CF and/or development of new therapeutic approaches for 
CF. Collectively, these projects should demonstrate essential
elements of unity and interdependence and result in a greater 
contribution to program goals than would occur if each project were 
pursued individually.  These centers provide support for research 
projects, pilot and feasibility studies, as well as common resources 
and facilities (cores) that are available to the individual projects 
comprising the program.  In order to be considered for funding, an 
application must have a minimum of three meritorious research projects.  
Each core must provide essential functions, services, techniques, 
determinations or instrumentation that will enhance at least two 
approved individual research projects.

A multidisciplinary approach to a research objective, which constitutes 
the central feature of the SCOR, is key to maintaining the rapid 
expansion of our knowledge of CF. The dramatic progress in 
understanding the molecular basis of CF has been due in large part to 
collaborations among scientists with expertise in physiology, cell 
biology, molecular biology, structural biology, genetics,
biochemistry, microbiology, and immunology.  While the identification 
of the gene that is mutated in CF sparked a rapid series of advances in 
understanding the function of CFTR, the complex interactions of CFTR 
with other membrane proteins is beginning to be uncovered.  In addition 
to its role as a chloride transporter, the important role of CTFR in 
regulating sodium and bicarbonate transport may be relevant to its 
pathophysiology. This central role of CFTR in regulation ion fluxes has 
made elucidating the pathophysiology of CF more difficult.  

Although 50 percent of CF patients in the general population are 
homozygous for the delta-F508 mutation, the severity of disease varies 
among homozygotes suggesting a role for genetic modifiers of the CF 
phenotype.  One such modifier gene that determines meconium ileus has 
been localized to chromosome 19 in humans. Further work is needed to 
identify this gene as well as other potential genetic modifiers. In 
addition, classes of CFTR mutations are correlated with isolated 
symptoms of pancreatitis, chronic rhinosinusitis and congenital 
bilateral absence of the vas deferens.  This enhanced ability to 
correlate phenotype and genotype will aid our ability to predict the 
severity of CF detected by genetic screening.

Ongoing work has elucidated the structural and functional domains of 
CFTR and the regulation of its channel activity through its 
interactions with other proteins. The membrane protein, syntaxin 1A, 
has been shown to interact with the tail of CFTR preventing its 
interaction with the regulatory domain thus inhibiting channel 
activity. This interdomain regulation may provide a mechanism that 
could be exploited for pharmacologic approaches to enhance the opening 
of the CFTR chloride channel.  In addition, CFTR binding to an 
accessory protein, CAP70, to form a CFTR dimer complex has been shown 
to enhance chloride channel activity.  

It is now recognized that many mutations, including delta-F508, alter 
the processing of CFTR, producing a misfolded protein that is retained 
and degraded in the endoplasmic reticulum.  Understanding of processing 
and trafficking of CFTR and how mutations affect interactions of CFTR 
with other cell components involved in trafficking and/or alter the 
ability of the protein to attain the proper three-dimensional structure 
is vital to development of strategies to stabilize and improve 
trafficking of mutant CFTR.

The mechanisms by which a defect in CFTR generates the complex 
pathophysiology of the disease require further definition.  CF affects 
multiple epithelial tissues resulting in characteristic lung disease, 
pancreatic insufficiency, biliary cirrhosis, meconium ileus, male 
infertility and elevated sweat chloride.  While the diverse pathology 
may be explained by defective chloride channel function, other 
mechanisms may also be involved.  CFTR belongs to a family of
transporters with multiple functions and potential roles for CFTR have 
been identified in a variety of cellular processes.  The potential 
impact of mutations in CFTR on these cellular processes must be 

Since the demonstration that transfection of the CFTR gene to CF 
epithelial cells corrects the chloride transport abnormality, 
development of safe and effective methods of gene therapy has become a 
major goal of CF research.  Development and optimization of gene
transfer systems are rapidly evolving, and CF has been at the forefront 
of the application of this new technology to treat clinical disease.  A 
variety of strategies employing viral-based vectors, liposomes and DNA 
conjugates are now being developed and tested for their ability to 
infect polarized cells.  Potential strategies to ameliorate harmful 
effects of vectors, such as immunologic responses, are being evaluated.  
Further work is needed to develop improved methods of gene delivery, 
leading to safe, stable and efficient gene transfer and expression in 
appropriate cells for gene therapy of CF.

Promising pharmacologic agents for the treatment of CF are under 
development.  These pharmacologic approaches include:  enhancing 
expression, folding and trafficking of mutant CFTR; increasing the 
activity of mutant CFTR; activating other membrane channels or cell 
processes to compensate for the defect in CFTR; and delivery of CFTR 
directly to affected cells.  Development and testing of new therapies 
is key to delaying or preventing the life-limiting complications of CF.

These are examples of research areas that would be considered 
responsive to this solicitation, and investigators may propose a 
variety of interrelated questions and approaches with the ultimate goal 
of enhancing our understanding of the pathogenesis of CF and ultimately 
finding new treatments for this devastating disease.


A special interaction between the centers and the NIDDK is anticipated.  
To foster this interaction as well as cooperation among centers, the 
NIDDK may arrange periodic meetings of center investigators.  
Applicants should indicate a willingness to participate in such 
meetings and request travel funds allocated for participation in such 


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 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification are 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 

All investigators proposing research involving human subjects should 
read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities 
as Subjects in Clinical Research," published in the NIH Guide for 
Grants and Contracts on August 2, 2000 
(; a 
complete copy of the updated Guidelines are available at  
The revisions relate to NIH defined Phase III clinical trials and 
require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, 
and to conduct and report analyses, as appropriate, by sex/gender 
and/or racial/ethnic group differences.


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

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

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.


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.


Prospective applicants are asked to submit, by October 15, 2001, 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) 594-8885
FAX:  (301) 480-3505


The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants.  These forms are available at most 
institutional offices of sponsored research and may be obtained from 
the Division of Extramural Outreach and Information Resources, National 
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 
20892-7910, telephone 301-710-0267, email:

All applicants should request a copy of Administrative Guidelines for 
Specialized Center of Research.  These guidelines contain important 
additional suggestions and information on the format, content, and 
review of applications and review criteria.  Prospective applicants may 
obtain guidelines from staff listed under INQUIRIES.

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application.  
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 
The sample RFA label available at: has been 
modified to allow for this change. Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the 
Checklist, three 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)

At time of submission, two additional copies of the application and all 
copies of appendix material must 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)

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 

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.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further 

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 National Diabetes and Digestive and Kidney Diseases Advisory 

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 

(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 support?

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 research.

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.


Letter of Intent Receipt Date:    October 15, 2001
Application Receipt Date:         November 13, 2001
Peer Review Date:                 February – March, 2002
Council Review:                   May 30-31, 2002
Earliest Anticipated Start Date:  September 1, 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:

Catherine McKeon, Ph.D.
Diabetes, Endocrinology and Metabolic Diseases Division
6707 Democracy Boulevard, Rm. 6103 MSC 5460
Bethesda, MD  20892-5460
Telephone:  (301) 594-8810
FAX:  (301) 480-3503

Direct inquiries regarding fiscal matters to:

Florence Danshes
Division of Extramural Activities
6707 Democracy Boulevard, Rm. 734 MSC 5456
Bethesda, MD  20892-5456
Telephone:  (301) 594-8861
FAX:  301-480-3504


This program is described in the Catalog of Federal Domestic Assistance 
No.  93.847.  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 

Return to Volume Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.