Full Text DK-94-002


NIH GUIDE, Volume 22, Number 35, October 1, 1993

RFA:  DK-94-002

P.T. 34

  Pulmonary Diseases 
  Biomedical Research, Multidiscipl 

National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  January 18, 1994
Application Receipt Date:  February 15, 1994


Cystic Fibrosis (CF) Research Centers will foster multidisciplinary
approaches to research ranging from elucidation of the molecular
pathogenesis of CF to development of new therapies for this disorder.


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 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 2000" (Full Report:  Stock No.
017-001-00474-0) or Healthy People 2000" (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 for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and
eligible agencies of the Federal government.  Minority individuals
and women are encouraged to submit as Principal Investigators.


Support of this program will be through the National Institutes of
Health (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.  Except as
otherwise stated in this announcement, awards will be administered
under PHS grants policy as stated in the PHS Grants Policy Statement.

The anticipated awards are for five years and are contingent upon the
availability of appropriated funds.  Applicants may not request more
than $750,000 in direct costs in any year.  The award date for these
grants will be September 30, 1994.


The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) expects to award up to four specialized centers of research
(P50) in fiscal year 1994 for research on cystic fibrosis.  The
receipt of four competitive continuation applications is anticipated,
and these applications will be in competition for the awards together
with other applications received in response to this announcement.
The total amount of available funds to support this program is
anticipated to be $2.3 million per year; however, this funding level
is dependent upon the receipt of a sufficient number of applications
of high scientific merit.  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


Cystic fibrosis (CF) is a devastating genetic disease affecting
approximately one in 2500 Caucasians.  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.  Life expectancy has increased to nearly 30 years due to
improvements in treatment of infection and therapy directed at the
pulmonary and nutritional complications of CF.  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 such as gene therapy, pharmacologic therapy and protein

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, molecular and structural biology,
genetics and biochemistry.  Multidisciplinary approaches are key to
maintaining the rapid expansion of our knowledge of CF.  Specialized
centers of research (P50) are for the support of a broadly-based
multidisciplinary or multifaceted research program that has a
well-defined major objective or central theme.  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.
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 both research
projects as well as common resources and facilities (cores) which are
available to the individual projects comprising the program.  An
application must have a least three meritorious research projects.
Cores must provide essential functions, services, techniques,
determinations or instrumentation that will enhance at least two
approved individual research projects.

SCOR grants 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.  Many critical questions remain to be
answered.  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. Clarification of the relationships between
mutations and CFTR structure and function may elucidate the
variations in disease severity among heterozygotes.  Additional
information is needed on molecular mechanisms that lead to defective
chloride transport, including the function of normal, non-mutated
CFTR and effects of mutations; regulation of CFTR activity;
processing and trafficking of CFTR; folding of CFTR and how mutations
alter the ability of the protein to attain the proper three-
dimensional structure.  Information in these areas will be vital for
development of strategies to stabilize or activate mutant CFTR.
Chloride channels other than CFTR are present in CF affected tissues
and a critical question for understanding how a defect in CFTR
generates the pathophysiology of the disease is how the loss of a low
conductance channel can cause the significant changes in salt
transport seen in CF.  The answer may lie in part in the relationship
between CFTR and other epithelial ion channels.  Moreover,
recruitment of alternative ion conductive pathways may have
therapeutic importance in CF, permitting strategies to circumvent the
chloride transport defect in CF.  CF is also characterized by
increased sodium absorption and the cellular basis of increased
sodium channel activity is unknown.

CF affects multiple epithelial tissues resulting in characteristic
lung disease, pancreatic insufficiency, biliary cirrhosis, meconium
ileus, male infertility and elevated sweat chloride.  Studies of
tissue specific expression of CFTR will elucidate its role in
development and organ function and dysfunction.   While this diverse
pathology may all 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 metabolic processes including hyperabsorption of
sodium and transport of molecules other than chloride, sulfation of
mucus, endosomal acidification, exocytosis and recycling of cell
membranes, as well as the predilection to pseudomonas infection.  The
potential impact of mutations in CFTR on these cellular processes is
under active investigation with the goal of elucidating the molecular
mechanisms underlying the CF phenotype.

Definition of the cellular and subcellar localization of CFTR within
affected tissues is critical both for understanding the
pathophysiology of CF and for developing strategies for gene and
pharmacologic therapy. Animal models are now at hand that may
facilitate investigation of both gene and pharmacologic therapy.
Development of safe and effective methods of gene therapy is a major
goal of CF research, and demonstration that transfection of the CF
gene corrects the chloride transport abnormality in affected
epithelial cells has established the feasibility of this approach.  A
variety of strategies employing viral vectors, liposomes and DNA
conjugates are now being developed and tested.  Further work is
needed to optimize vectors, promoters, and techniques for obtaining
safe, stable and efficient gene transfer into appropriate cells for
gene therapy of CF; to identify cells that are appropriate targets
for gene therapy; to study processes involved in the expression
and/or over-expression of the CF gene and the functional consequences
of constitutive CFTR expression; and to identify potential hazards of
gene therapy.  These are examples of research areas which 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.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them. This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Item 4 (Research Design and Methods) of the Research
Plan AND summarized in Item 5, Human Subjects.  Applicants are urged
to assess carefully the feasibility of including the broadest
possible representation of minority groups.  However, NIH recognizes
that it may not be feasible or appropriate in all research projects
to include representation of the full array of United States
racial/ethnic minority populations; i.e., Native Americans [including
American Indians or Alaskan Natives], Asian/Pacific Islanders,
Blacks, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these


Prospective applicants are asked to submit, by January 18, 1994, 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 subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIDDK staff to estimate the potential review
workload and to avoid possible 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
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083


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 below early in the preparation of the
application.  Specific instructions for preparing a SCOR application
should be requested.

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/435-0714.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page.  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 check the YES box.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by February 15, 1994.  If an
application is received after that date, it will be returned to the
applicant.  If the application submitted in response to this RFA is
substantially similar to a grant application already submitted to the
NIH for review, but has not yet been reviewed, the applicant will be
asked to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be
allowed, nor will essentially identical applications be reviewed by
different review committees.  Therefore, an application cannot be
submitted in response to this RFA that is essentially identical to
one that has already been reviewed.  This does not preclude the
submission of substantial revisions of applications already reviewed,
but such applications must include an introduction addressing the
previous critique.  However, it is allowable to submit the same
project as both an R01 and as a component project of a SCOR.


Upon receipt, applications will be initially reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIDDK staff function.  If the application is not responsive
to the RFA, NIDDK staff will contact the applicant to withdraw the

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK.  If
the number of applications is large compared to the number of awards
to be made, a preliminary scientific peer review may be conducted and
applications withdrawn from further competition when they are judged
to be non-competitive for the award.  The NIDDK will notify the
applicant and institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened
for this RFA.  Following this review, the applications will be given
a secondary review by the NIDDK Advisory Council unless not
recommended for further consideration by the initial review group.

The major factors to be considered in the evaluation of applications
will be:

o  scientific/technical merit specific to the objectives of the RFA
of the program as a whole as well as that of each proposed project,
including the novelty, originality, feasibility and the adequacy of
the experimental design;

o  significance of the overall program goals;

o  scientific gain of combining the component parts into a
specialized center (beyond that achievable if each project were to be
pursued separately);

o  cohesiveness and multidisciplinary scope of the program and the
coordination and interrelationship of all individual research
projects and cores to the common theme;

o  the technical merit and the justification of core units designed
to support the research project components of the center;

o  leadership and scientific ability of the Principal
Investigator/program director and his or her commitment and ability
to develop a well-defined central research focus and to devote
adequate time and effort to the program;

o  the competence of the investigators to accomplish the proposed
research goals, and the adequacy of their time commitments to the

Additional criteria for competing continuation (renewal) applications

o  progress and achievements specific to this center since its
inception and the documentation through publications, conferences,
etc., that collaboration has occurred;

o  previous performance and use of the cores;

o  justification for adding new projects or cores or for deleting
components previously supported.

Administrative factors that will be considered in the evaluation of
applications include:

o  academic environment and resources in which the research will be
conducted, including availability of space, equipment, human
subjects, animals or other resources as required, and the potential
for interaction with scientists from other departments;

o  institutional commitment to the requirements of the program,
including fiscal responsibility and management capability of the
institution to assist the principal investigator/program director and
his or her staff in following DHHS, PHS, and NIH policy;

o  administrative planning and leadership capability to provide for
internal quality control of ongoing research, allocation of funds,
enhancement of internal communication and cooperation among the
investigators involved in the program, and the replacement of the
Principal Investigator/program director if required on an interim or
permanent basis;

o  appropriateness of the proposed budget and duration in relation to
the proposed research; and

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.


The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review.
o  Availability of funds.
o  Balance among research areas covered by the NIDDK CF Centers

The anticipated date of award is September 30, 1994.


Written and telephone inquiries concerning this RFA are encouraged.

Direct inquiries regarding programmatic issues to:

Judith E. Fradkin, M.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 621
Bethesda, MD  20892
Telephone:  (301) 594-7567

Direct inquiries regarding fiscal matters to:

Linda M. Stecklein
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 653
Bethesda, MD  20892
Telephone:  (301) 594-7543


Letter of Intent Receipt Date:  January 18, 1994
Application Receipt Date:       February 15, 1994
Initial Review:                 May 1994
Second Level Review:            September 1994
Anticipated Date of Award:      September 30, 1994


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


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