Full Text DK-95-006


NIH GUIDE, Volume 24, Number 12, March 31, 1995

RFA:  DK-95-006

P.T. 34

  Pulmonary Diseases 
  Biology, Cellular 
  Biology, Molecular 

National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung, and Blood Institute
Cystic Fibrosis Foundation

Letter of Intent Receipt Date:  October 24, 1995
Application Receipt Date:  November 28, 1995


This Request for Applications (RFA) is intended to foster development
of new therapies for cystic fibrosis (CF) through support of basic
research on the pathogenesis of cystic fibrosis and its
complications, application of advances in cell and molecular biology
to understanding CF, translation of basic research into new
treatments for CF, and clinical research on CF and its potential


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,
Pathogenesis and Treatment of Cystic Fibrosis, 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: 202/783-3238).


Applications may be submitted by domestic and foreign 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 research project
grant (R01) 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.

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 total requested project period
for applications submitted in response to this RFA may not exceed
four years.  A maximum of three years can be requested for foreign
awards.  The maximum dollars that may be requested is limited to
$160,000 in direct costs for the initial budget period with budget
escalations in future years are limited to four percent over the
initial budget period.  The anticipated award date is July 1, 1996.

Projects with substantial scientific merit that are not funded by the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) or the National Heart, Lung, and Blood Institute (NHLBI) are
eligible for support by the Cystic Fibrosis Foundation (CFF).
Principal investigators will be responsible for forwarding copies of
their summary statements and applications to the CFF for
consideration for this award mechanism.  The amount of  CFF support
will be determined by project scope and duration of funding will be
limited to two years.  No funds for indirect costs will be provided.


For FY 1996, $2 million (total costs) will be committed by the NIDDK
and $1 million will be committed by the NHLBI to fund applications
submitted in response to this RFA.  It is anticipated that
approximately 15 awards will be made.  An additional $2 million will
be committed by the CFF to fund applications not funded by NIDDK or
NHLBI.  However, these funding levels are dependent upon the receipt
of a sufficient number of applications of high scientific merit.
Applicants must limit their requests to not more than $160,000 direct
costs for the initial budget period and to four percent annual budget
escalations in future years.  Although this program is provided for
in the financial plans of the NIDDK and the NHLBI, the award of
grants pursuant to this RFA is also contingent upon the availability
of funds for this purpose.



In the past three decades, improvements in clinical management of CF
have increased the median survival from under five years to nearly
thirty years.  This improvement has largely resulted from improved
management of infection, pulmonary secretions and nutrition.  The
identification, in 1989, of the gene that is mutated in CF sparked a
rapid series of advances in understanding the molecular
pathophysiology of CF.  The function of the gene product, the Cystic
Fibrosis Transmembrane Regulator (CFTR), as a chloride channel has
been established and over 400 mutations have been identified.
Ongoing work is elucidating the structure and functional domains of
CFTR, probing the complex regulation of its activity as a channel,
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 of chloride channels in addition to
CFTR suggests additional strategies for pharmacologic amelioration of
this disorder.  It is now recognized that many mutations, including
the most common mutation causing CF, alter the processing of CFTR,
producing a misfolded protein that is retained and degraded in the
endoplasmic reticulum.  Strategies to stabilize and improve
trafficking of mutant CFTR could overcome this defect.  Particularly
exciting has been the finding that expression of normal CFTR can
correct the chloride transport defect in affected CF epithelia.
Development and optimization of gene transfer systems is rapidly
evolving and CF has been at the forefront of the application of this
new technology to the treatment and cure of clinical disease.
Through the development of gene therapy and new pharmacologic
approaches for treatment or cure of CF we may reap the full clinical
benefits from the identification of the CF gene.

This RFA is designed to address the molecular pathogenesis and the
pathophysiology of CF and its complications, and to develop new
approaches to therapy.  Areas of research that would be responsive
include, but are not limited to:

Elucidation of the relationship between individual mutations and the
clinical phenotype, and the molecular mechanisms by which mutations
cause dysfunction;

Identification of genetic or environmental factors that explain the
variable clinical presentations and severity of disease associated
with a given mutation;

Studies of processing, trafficking and folding of CFTR, and the
mechanisms by which specific mutations alter these events and the
structure and cellular location of CFTR;

Exploration of strategies to stabilize mutant CFTR and enhance its
targeting to the cell membrane;

Studies on regulation of CFTR activity, the mechanisms by which
mutations alter CFTR function, and strategies for enhancing function
of mutant CFTR;

Elucidation of the pathways of electrolyte transport in affected
epithelia, the relationship between CFTR and other epithelial ion
channels, and the mechanism by which the rate of sodium transport is
increased in CF;  Identification and characterization of alternate
chloride channels which might be activated to circumvent the chloride
transport defect in CF;

Exploration of potential roles of CFTR in 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, as well as exploration of the mechanisms
by which mutations in CFTR may affect these processes;

Studies of tissue specific expression of CFTR, and definition of the
cellular and subcellular localization of wildtype and mutant CFTR
within affected tissues, to elucidate the pathophysiology of CF and
aid the development of strategies for gene and pharmacologic therapy;

Development of safe and effective methods for gene therapy, including
identification, characterization and optimization of suitable vectors
and promoters, development of improved methods of gene delivery,
identification of potential hazards of gene therapy, and testing gene
therapy in vitro, in animal models and in human subjects.

Delineation of the mechanisms underlying the inflammation and
infection characteristic of CF and how mutations in the CF gene and
alteration in CFTR function result in inflammation and infection;

Studies of the pathophysiologic mechanisms underlying malnutrition
and growth failure in CF, the relationship between pulmonary
function, infection and nutritional status, and the extent to which
achievement of normal nutrition and growth might ameliorate the rate
of progression of lung disease and improve survival, and development
and testing of strategies to improve nutritional status in CF;

Studies of the pathophysiologic mechanisms underlying other
complications of CF, such as increased risk of gastrointestinal
malignancy, impaired fertility, liver disease, and diabetes, and
development and testing of strategies to prevent or ameliorate these

These are examples of areas of research that are responsive to this
solicitation and are not listed in order of priority.  Investigators
are free to propose additional areas of investigation responsive to
the purpose of the RFA.


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 24, 1995, 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 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 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
Natcher Building, Room 6AS-37F
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8886
FAX:  (301) 480-3505
E-mail:  hammondr@ep.niddk.nih.gov


The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The forms are available from most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD  20892,
telephone, 301/710-0267; and from the program administrator listed

The RFA label available in the PHS 398 (rev. 9/91) 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 2a 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, and three signed photocopies, in one package to:

Division of Research Grants
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
Natcher Building, Room 6AS-37F
BETHESDA, MD  20892-6600

Applications must be received by November 28, 1995.  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.


Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NIDDK and the NHLBI.  Incomplete
applications will be returned to the applicant without further
consideration.  If the application is not responsive to the RFA,
NIDDK and NHLBI staff will contact the applicant to determine whether
to return the application to the applicant or submit it for review in
competition with unsolicited applications at the next review cycle.
Additional information will not be accepted after the official
receipt date unless approved by the Scientific Review Administrator.

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, a process (streamlining) may be
used by the initial review group in which applications will be
determined to be competitive or non- competitive based on their
scientific merit relative to other applications received in response
to the RFA. Applications judged to be competitive will be discussed
and be assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator and the official signing for the applicant
organization will be notified.

Review Criteria

o  scientific/technical merit criteria specific to the objectives of
the RFA;

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed

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 budget duration in
relation to the proposed research; and

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

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

Additional criterion for foreign applications:

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 that provide augmentation of
existing U.S. resources.


The anticipated date of award is July 1, l996.  The following factors
will be used to make award decisions: scientific merit as determined
by peer review, availability of funds, and 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:

Judith Fradkin, M.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 5AN-12E
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8814
FAX:  (301) 480-3503
E-mail:  fradkinj@ep.niddk.nih.gov

Susan Banks-Schlegel, Ph.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 10018
6701 Rockledge Drive
Bethesda, MD 20892
Telephone:  (301) 435-0202
FAX:  (301) 480-3557

Direct inquiries regarding fiscal and administrative matters to:

Usha Ganti
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, 6AS-49B
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8868
FAX:  (301) 480-3504
E-mail:  gantiu@ep.niddk.nih.gov

Tanya T. McCoy
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
2 Rockledge Center, Room 7148
6701 Rockledge Drive
Bethesda, MD  20892
Telephone:  (301) 435-0171
FAX:  (301) 480-3310


This program is described in the Catalog of Federal Domestic
Assistance No. 93.847, Diabetes, Endocrinology, and Metabolism and
No. 93.838, Lung Diseases Research. Awards are made under the
authority 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 routing 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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