Full Text HD-94-005

PATHOPHYSIOLOGY OF NECROTIZING ENTEROCOLITIS

NIH Guide, Volume 22, Number 17, April 30, 1993

RFA:  HD-94-005

P.T. 34

Keywords: 
  Pathophysiology 
  Digestive Diseases & Disorders 
  Disease Prevention+ 
  Etiology 


National Institute of Child Health and Human Development

Application Receipt Date:  September 8, 1993

PURPOSE

The Endocrinology, Nutrition and Growth Branch and the Pregnancy and
Perinatology Branch of the Center for Research for Mothers and Children
of the National Institute of Child Health and Human Development (NICHD)
herewith issue a Request for Applications (RFA) on the pathophysiology
of necrotizing enterocolitis (NEC).

Neonatal nutrition is one of the most important research programs of
the NICHD, especially from a prevention viewpoint.  By soliciting
research grant applications that focus on the cellular and molecular
mechanisms that lead to the morbidity and mortality of NEC, the NICHD
hopes to develop an understanding of the disease process which will
allow clinicians to reason backward to its etiology and prevention.

The purpose of this RFA is to encourage investigators working on
gastrointestinal circulatory dynamics, cytokines, immune mechanisms,
and other areas of basic physiology and biochemistry to devote their
expertise to studies of pathophysiological processes which could be
involved in the generation of NEC.  It is postulated that one or more
of these approaches will lead to clues to the etiology, prevention, and
therapy of this disorder.

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, The
Pathophysiology of Necrotizing Enterocolitis (NEC), is related to the
priority areas of nutrition and maternal and infant health.  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).

ELIGIBILITY REQUIREMENTS

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.
Applications from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

Applications in response to this RFA will be funded through the
individual research grant (R01) program of the NIH.  This announcement
is for a single competition with the application receipt deadline of
September 8, 1993.  Future unsolicited competing continuation
applications will compete with all investigator- initiated applications
and be reviewed by a Division of Research Grants (DRG) study section.
However, if the NICHD determines that there is a sufficient continuing
program need, the NICHD may announce a request for competitive
continuation applications.  The total project period for applications
submitted in response to the present RFA should not exceed five years.
The earliest anticipated award date is April 1, 1994.

FUNDS AVAILABLE

It is anticipated that four grants will be awarded under this program,
contingent upon receipt of a sufficient number of meritorious
applications and the availability of funds.  To fund these awards
$600,000 has been set aside for direct costs in the first year.

RESEARCH OBJECTIVES

Background

NEC is a disease of unknown etiology which predominantly affects
premature infants after they begin enteral nutrition.  It is estimated
that between 3000 to 4000 cases of NEC occur annually and that the
mortality is between 10 to 40 percent.  The incidence and case fatality
ratio are highest in the smallest premature infants and decrease with
advancing gestational age, but about 10 percent of patients are
full-term.

NEC occurs often in infants who have survived the earlier diseases
associated with prematurity:  respiratory distress syndrome, patent
ductus arteriosus, asphyxia, etc.  Many infants become affected days,
weeks, or even months after birth, when they seem to be doing well.
With the advent of modern neonatal technologies, such as surfactant,
high frequency ventilation, and intravenous immunoglobulin, more
premature infants may survive the acute illnesses related to preterm
birth and become at risk for NEC.  Fear of NEC also has strong
developmental and economic impacts, since it often leads caretakers to
delay the onset of feeding in the smallest infants, delaying their
growth and hospital discharge.

NEC occurs as a sporadic, endemic disease, or in epidemic outbreaks.
Despite many epidemiologic studies, there have been no consistently
identifiable pathogens associated with these outbreaks.  Indeed, in
most epidemics, no enteric pathogen at all has been recovered.
Nevertheless, neonatal intensive care unit (NICU) personnel frequently
complain of nonspecific gastrointestinal symptoms during epidemics of
NEC.  Furthermore, other neonatal patients may demonstrate diarrhea or
hematochezia and distention, but not NEC, during epidemics of NEC in
the NICU.  These epidemiologic characteristics of the condition have
suggested that NEC is due to an unidentified infectious agent or
agents.  It is not even known, however, whether the pathogenesis of the
manifestations of NEC is immunologic, toxic, circulatory, behavioral,
developmental, or some combination of these.

Objectives and Scope

The NICHD seeks to create linkages between basic science laboratories
capable of molecular studies and investigators of the clinical entity
NEC.  This is to allow exploration of the idea that many different
kinds of neonatal insult could lead to a final common pathway of
intestinal damage.  Sample processing with DNA probes or other
applications of molecular biology might produce an understanding of the
initiating event (etiology) in the development of NEC; nevertheless,
later components of the pathogenesis of NEC also need attention, which
may require further development of minimally-invasive methods to
investigate human pathophysiology.  Until that time, or as a part of
the development of such methods, appropriate animal models and tissue
culture systems could be used to identify the alterations of mucosal
and immune host defense that may contribute to the increased
susceptibility of the premature infant to this condition.
Developmental aspects of mucosal function, local immune responses (IgA,
cytokines, monocytes), and repair mechanisms could be critical aspects
of these investigations.

This RFA includes animal model, tissue culture, and other in vitro
studies.  It also includes studies of molecular immunology and such
clinical studies as might bear on the pathogenesis of NEC.  It does not
include clinical studies of epidemiology, that are already being
addressed, or tests of hypotheses of etiology which do not address
pathogenesis experimentally.  Trials of therapy which bypass
preliminary studies of pathogenesis to provide a rationale for them
will also not be supported through this RFA.  Nevertheless, clinical
studies are not excluded if they address disease mechanisms.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

It is expected that most applications funded in response to this RFA
will involve animal models or in vitro systems.  If clinical studies
are submitted, NIH policy is that applicants for NIH clinical research
grants and cooperative agreements will be required to include
minorities 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 should be placed on the need for
inclusion of minorities 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 minorities are
excluded or inadequately represented in clinical research, particularly
in proposed population-based studies, a clear and compelling rationale
should be provided.

The racial/ethnic composition of the proposed study population must be
described.  In addition, racial/ethnic issues should be addressed in
developing a research design and sample size appropriate for the
scientific objectives of the study.  This information should be
included in the form PHS 398 (rev.9/91) in Sections 1-4 of the Research
Plan AND summarized in Section 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 includes 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 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, 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 minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
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 will be 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 policies.

APPLICATION PROCEDURES

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

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 an 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 checked.

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

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

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

Susan Streufert, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Building, Room 5E01
Bethesda, MD  20892

Applications must be received by September 8, 1993.  If an application
is received after that date, it will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  If the application submitted in response to this
RFA is substantially similar to a research grant application already
submitted to the NIH for review, that 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.

REVIEW CONSIDERATIONS

Applications will be reviewed by NICHD staff for responsiveness to the
RFA.  Applications judged to be nonresponsive will be returned.  The
applicant may resubmit the application and have it assigned for review
in the same manner as unsolicited grant applications.

Responsive applications may be subjected to a triage by a peer-review
group to determine their scientific merit relative to the other
applications received in response to this RFA.  NIH will withdraw from
competition those applications judged to be noncompetitive and notify
the applicant and institutional business official.  Those applications
judged to be competitive will be further evaluated for
scientific/technical merit by a review group convened solely for this
purpose by the Division of Scientific Review, NICHD.  Criteria for the
initial review will include the significance and originality of
research goals and approaches; the feasibility of research and adequacy
of the experimental design; the research experience and competence of
the investigator(s) to conduct the proposed work; the adequacy of
investigator effort devoted to the project; and the appropriateness of
the project duration and cost relative to the work proposed.  Following
review by the Initial Review Group, applications will be evaluated by
the National Advisory Child Health and Human Development Council for
program relevance and policy issues before awards for meritorious
proposals are made.

AWARD CRITERIA

The anticipated award date is April 1, 1994.  Scientific merit and
technical proficiency, based on the demonstrated and projected
capabilities described in the application in response to the RFA, will
be the predominant criteria for determining funding priorities.

INQUIRIES

Written and telephone 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:

Ephraim Y. Levin, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Building, Room 4B11
Bethesda, MD  20892
Telephone:  (301) 496-5593

Direct inquiries regarding fiscal matters to:

Mr. E. Douglas Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
6100 Building, Room 8A17
Bethesda, MD  20892
Telephone:  (301) 496-1303

AUTHORITY AND REGULATIONS

This program is described in the catalog of Federal Domestic Assistance
No. 93.865, Research for Mothers and Children.  Awards will be made
under the authority of the Public Health Service Act, Section 301 (42
USC241), and administered under PHS grants policies and Federal
Regulations 42 CFR Part 52 and 45 CFR Part 74.  This program is not
subject to review by a Health Systems Agency.

.

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