Full Text DK-96-010
NIH GUIDE, Volume 25, Number 8, March 15, 1996
RFA:  DK-96-010
P.T. 04

  Pulmonary Diseases 
  Treatment, Medical+ 

National Institute of Diabetes and Digestive and Kidney Diseases
Letter of Intent Receipt Date:  October 8, 1996
Application Receipt Date:  November 13, 1996
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 one award will be made related to this Request for
Applications (RFA) in FY 1997.  The receipt of one competing
continuation application is anticipated, and this application will be
in competition for the award 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 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Cystic Fibrosis Research Center, 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).
Applications may be submitted by for-profit and non-profit
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.
Support of this program will be through the NIH Specialized Center of
Research (SCOR) (P50) award.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  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 anticipated award is for
five years, contingent on the availability of funds.  The maximum
dollar request is limited to $750,000 in direct costs in any year.
The anticipated award date is September 1, 1997.
In FY 1997, it is anticipated that $727,000 in total costs will be
committed to fund an application submitted in response to this RFA;
however, this funding level is dependent upon the receipt of an
application of high scientific merit.  Applicants must limit their
requests to not more than $750,000 direct costs in any 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.
Improved therapy has transformed CF from a disease characterized by
death in early childhood to a chronic illness with a median survival
of nearly 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) are for the support of
broadly-based multi disciplinary or multifaceted research programs
that have well-defined major objectives or central themes.  They are
directed toward a range of scientific questions having a central
research focus.  They provide for integration of efforts of
independent scientists investigating various aspects of the central
theme.  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 and of the function of the gene
product as a chloride channel sparked a rapid series of advances in
understanding the molecular pathophysiology of CF, many critical
questions remain to be answered.  Over 400 mutations have been
identified and molecular mechanisms by which specific mutations 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  F508
mutation, the severity of disease varies among homozygotes,
suggesting a role for other genetic or environmental factors.
Ongoing work is elucidating the structure and functional domains of
CFTR, probing the regulation of its channel activity, and defining
the molecular and cellular basis by which mutations 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 identification of abnormal sodium permeability
in CF and elucidation of the relationship between CFTR and other
epithelial ion channels suggest additional strategies for
pharmacologic amelioration of this disorder.  It is now recognized
that many mutations, including  F508, alter the processing of CFTR,
producing a misfolded protein that is retained and degraded in the
ER.  Understanding of processing and trafficking of CFTR and how
mutations 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.
A critical question remains how a defect in CFTR generates the
complex pathophysiology of the disease.  CF affects multiple
epithelial tissues resulting in characteristic lung disease,
pancreatic insufficiency, biliary cirrhosis, meconium ileus, male
infertility and elevated sweat chloride.  Tissue specific expression
of CFTR, the cellular and subcellular localization of wildtype and
mutant CFTR within affected tissues, the role of CFTR in the
development and function of specific cells and tissues, the pathways
of electrolyte transport in affected epithelia, and the relationship
between CFTR and other epithelial ion channels require further
exploration.  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.  CFTR has been linked to a variety of cellular processes,
such as transport of molecules other than chloride, posttranslational
processing of mucins and other proteins, endosomal acidification and
other aspects of subcellular organelle function, exocytosis, and
recycling of cell membranes.  The potential impact of mutations in
CFTR on these cellular processes must be explored. Delineation of the
mechanisms underlying the inflammation and infection characteristic
of CF and the predilection to pseudomonas infection will also
elucidate the molecular mechanisms underlying the CF phenotype.
Since demonstration that transfection of the CFTR gene corrects the
chloride transport abnormality in affected epithelial cells,
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.
Toxic effects of vectors including immunologic responses are being
evaluated, and potential strategies to ameliorate them are being
identified.  The cells that are appropriate targets for gene therapy
in CF must be identified.  Further work is needed to develop suitable
vectors and promoters, to improve methods of gene delivery, leading
to safe, stable and efficient gene transfer and expression in
appropriate cells for gene therapy 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.
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.
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 new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
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 reprinted
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
Prospective applicants are asked to submit, by October 8, 1996, 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
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 37-E - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505
Because of the size and complexity of a SCOR, prospective applicants
are urged to take advantage of the opportunity to consult with
program staff listed under INQUIRIES early in the preparation of the
application.  Specific instructions for preparing a SCOR application
should be requested.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95).  Application kits are available at most
institutional offices of sponsored research and may be obtained from
the Office of Extramural Outreach and Information Resources, Office
of Extramural Programs, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267,
email: girg@drgpo.drg.nih.gov.
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:
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 37-E, MSC 6600
Bethesda, MD  20892-6600
Applications must be received by November 13, 1996.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) 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 DRG 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.
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 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
o  Significance of the research as related to the objectives of the
RFA as set forth in the RESEARCH OBJECTIVES section above;
o  general scientific, technical, or medical significance and
originality of proposed research;
o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;
o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively in the area
of the proposed research;
o  availability of resources necessary to perform the research;
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; and
o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries that are not readily
available in the United States or which provide augmentation of
existing U.S. resources.
The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.
The anticipated date of award is September 1, l997.  The following
will be considered in making funding decisions:
o  scientific merit as determined by peer review,
o  availability of funds, and
o  balance among research areas covered by the NIDDK CF Centers
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 Metabolism
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 5AN-12E
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
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8848
Email:  hugginsd@ep.niddk.nih.gov
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
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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