CYSTIC FIBROSIS RESEARCH CENTER

Release Date:  February 20, 1998

RFA:  DK-98-011

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  October 20, 1998
Application Receipt Date:  November 20, 1998

PURPOSE

Cystic Fibrosis (CF) Research Centers will 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 three
awards will be made in response to this Request for Applications (RFA) in FY
1999.  The receipt of three competing continuation applications is anticipated,
and these applications will be in competition together with other applications
received in response to this RFA.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This RFA, Cystic Fibrosis Research Centers,
is related to the priority area of chronic diseases.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0
or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325 (telephone: 202-
512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public or 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.

MECHANISM OF SUPPORT

Support of this program will be through the NIH Specialized Center of Research
(SCOR) grant (P50) award.  Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the applicant.  Except
as otherwise stated in this RFA, awards will be administered under PHS grants
policy as stated in the PHS Grants Policy Statement.

Applicants from institutions that 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.  If so, a letter of
agreement from either the GCRC program director or principal investigator should
be included with the application.

This RFA is a one-time solicitation.  The NIDDK only accepts new and competing
continuation SCOR applications in response to an RFA.  The total requested
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, 1999.

FUNDS AVAILABLE

For FY 1999, $2.9 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that three awards will be made, and
receipt of three competing continuation applications is anticipated.  However,
this funding level is dependent upon the receipt of a sufficient number of
applications of high scientific merit.  In order to help meet the goals of NIDDK
for managing the costs of biomedical research, applicants must limit their
requests to not more than $750,000 direct costs for each budget period.  Although
this program is provided for in the financial plans of the NIDDK, the award of
grants pursuant to this RFA is also contingent upon the availability of funds for
this purpose.

RESEARCH OBJECTIVES

Improved therapy has transformed CF from a disease characterized by death in
early childhood to a chronic illness with a median survival of approximately 30
years.  However, there is still no cure for this devastating genetic disease
affecting approximately 30,000 Americans.  Since the cloning of the CF gene and
identification of its protein product as a cAMP-regulated chloride channel,
molecular understanding of this disorder has progressed rapidly.  Nonetheless
many questions about molecular pathogenesis, with important implications for
therapy, remain to be answered.  The challenge now is to further define the
molecular mechanisms underlying CF and to translate information about the
molecular basis of disease into new treatments.

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) which 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.  Cores 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
molecular pathophysiology of CF, many critical questions remain to be answered. 
Over 600 mutations have been identified and molecular mechanisms by which
specific mutations and polymorphisms cause dysfunction have been clarified, yet
the relationship between genotype and phenotype remains obscure.  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 other genetic or environmental factors.

Ongoing work is elucidating the structural and functional domains of CFTR,
probing the regulation of its channel activity, and defining the molecular and
cellular basis by which mutations and polymorphisms in CFTR cause clinical
disease. This work provides the basis for rational design of pharmacologic
approaches to enhance the opening of the defective CFTR chloride channel.  The
elucidation of the relationships between CFTR and other epithelial ion channels
suggests additional strategies for pharmacologic amelioration of this disorder. 
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 explored.

Delineation of the mechanisms underlying the inflammation and infection and the
predilection to pseudomonas colonization characteristic of CF is essential for
developing strategies for preventing or limiting the pulmonary disease, which is
the major cause of death in people with CF.  The identification of human
antimicrobial peptides, particularly human beta defensin-1 in the airway, and the
observation that the antimicrobial activity of airway fluid is impaired in CF
have important implications for new therapeutic approaches.  Important questions
remain about the role of CFTR in determining the composition of the airway
surface liquid (ASL) and how alterations in ASL in CF may affect lung defense.

Since the demonstration that transfection of the CFTR gene to CF epithelial cells
corrects the chloride transport abnormality, and more recently that it restores
antimicrobial activity, 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.  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.

A number of important new therapies, including aerosolized tobramycin, DNase ,
and ibuprofen, have been shown to ameliorate the infection and inflammation of
CF.  Other promising pharmacologic agents are under development.  These
pharmacologic approaches include:  enhancing expression, folding and trafficking
of mutant CFTR; increasing the activity of mutant CFTR; altering other membrane
channels or cell processes to compensate for the defect in CFTR; and delivery of
proteins, such as defensins that are effective in the CF airway or even CFTR
itself, directly to the affected airway.  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 curing this devastating disease.

SPECIAL REQUIREMENTS

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 meetings.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

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 is provided 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 research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513), and in the NIH GUIDE FOR GRANTS AND CONTRACTS, Volume 23,
Number 11, March 18, 1994.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 20, 1998, 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 avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) 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:
asknih@od.nih.gov.

Supplemental guidelines for preparing SCOR applications are available from staff
listed under Inquiries below.

The RFA label available in the PHS 398 (rev. 5/95) 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 marked.

Submit a signed, typewritten original of the application, including the
Checklist, plus 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 must be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F, MSC 6600
Bethesda, MD  20892-6600

Applications must be received by November 20, 1998.  If an application is
received after that date, it will be returned to the applicant without 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.  Projects that are components of
the SCOR application may be submitted as separate R01 applications.

REVIEW CONSIDERATIONS

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened in
accordance with NIH peer review procedures.  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 will be
discussed, assigned a priority score, and receive a second level review by the
National Diabetes and Digestive and Kidney Diseases Advisory Council.

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 review, comments on the following aspects of the application will be made
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 the assignment of the overall score.

o  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?

o  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?

o  Innovation:  Does the project employ novel concepts, approaches or method? Are
the aims original and innovative?  Does the project challenge existing paradigms
or develop new methodologies or technologies?

o  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)?

o  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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

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

The initial review group will also examine the provisions for the protection of
human and animal subjects, and the safety of the research environment.

AWARD CRITERIA

The anticipated date of award is September 1, 1999.

These factors will be used to make award decisions: scientific and technical
merit as determined by peer review, availability of funds, programmatic
priorities and balance among research areas addressed by the NIDDK CF Centers
Program.

INQUIRIES

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:

Judith Fradkin, M.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8814
FAX:  (301) 480-3503
Email:  FradkinJ@ep.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Donna Huggins
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
BETHESDA, MD 20892-6600
Telephone:  (301) 594-8848
Email:  hugginsd@ep.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93..847.  Awards are made 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 PHS grants policies and Federal Regulations 42
CFR 52 and 45 CFR Part 74.  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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