Full Text HD-94-011

DIAGNOSTIC METHODS TO ASSESS NEUROLOGIC INTEGRITY IN FETUS/NEONATE

NIH GUIDE, Volume 23, Number 5, February 4, 1994

RFA:  HD-94-011

P.T. 34

Keywords: 
  Neurophysiology 
  Diagnosis, Medical 
  Fetus 
  0775013 


National Institute of Child Health and Human Development
National Institute of Neurological Disorders and Stroke

Application Receipt Date:  April 29, 1994

PURPOSE

The objective of the RFA is to stimulate research on the development
of effective technologies to assess the integrity and function of the
developing brain in the human fetus and newborns.  The long-term goal
of this research is the identification of newborns with brain
dysfunction due to early, repetitive or chronic intrauterine central
nervous system (CNS) influences/insults, which may result in Sudden
Infant Death Syndrome (SIDS) and developmental disabilities including
cerebral palsy.  Postnatally acquired and acute perinatal deficits
are not within the scope of this RFA.  The National Institute of
Child Health and Human Development (NICHD) and the National Institute
of Neurological Disorders and Stroke (NINDS) invite applications for
studies in animals and/or humans that (1) elucidate the physiological
parameters that would serve as reliable markers of central nervous
system integrity/pathology; and (2) explore the development of
technologies/clinical tools that might identify infants who have, or
are at risk for, abnormal neurologic development or sudden death from
prenatal insults.

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 Request
for Applications (RFA), Assessment of the Nervous System in the Fetus
and Newborn, is related to the priority area of 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.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) awards.  Applications
from minority individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and FIRST Award (R29).  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  The total project period for R01
applications submitted in response to the present RFA may not exceed
four years.  R29 awards must be for five years.  The earliest
anticipated award date is September 30, 1994.

Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the size of an award will
vary also. 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.

FUNDS AVAILABLE

The estimated direct costs available for the first year of support
for the entire program is $800,000 from the NICHD and $600,000 from
NINDS.  The anticipated number of new awards supported is four by
NICHD and three by NINDS.

RESEARCH OBJECTIVES

Background

Identification of infants at risk for abnormal neurologic development
is a daunting clinical problem.  It is increasingly clear that acute
perinatal "asphyxia" accounts for a minor proportion of infants with
abnormal neurologic outcome.  Many more infants appear normal at
birth but seem to have sustained as-yet poorly understood fetal
insults.

Although there is an imprecise understanding of the relationship
between fetal insults and cellular events, there is general agreement
that a hypothetical sequence of cellular events may occur by which
hypoxia or ischemia may become cytotoxic.  Work in animal models is
clarifying the mechanisms operative in hypoxic-ischemic neuronal
damage and has identified a number of potentially therapeutic
interventions.  An insult may cause immediate or delayed neuronal
death or injury.  A number of factors, including infectious agents,
drugs, immune status, neuroendocrine status, etc., appear capable of
influencing the developing brain's maldevelopment and vulnerability,
and response to injury.  The nature, degree, length, frequency, and
reversibility of these influences, as well as genetic vulnerability
of the fetus may determine the relative importance of the mechanisms
and the location and severity of the deficits.

The purpose of this solicitation is to develop methods to identify
clinical parameters that may be used to define the fetus or newborn
infant at risk for abnormal nervous system functioning as a result of
fetal insult or maldevelopment.  These parameters could include fetal
markers in all three trimesters, and/or clinical parameters from the
neonatal period.  Manifestations of abnormal nervous system
development include autonomic and state dysfunction that may lead to
SIDS, sensory dysfunction, cerebral palsy or later cognitive
disability.  The ultimate goal is to define clinically useful
parameters to identify the fetus or neonate who would benefit from
the application of preventative and therapeutic interventions within
an appropriate window of opportunity.

Development of tools to evaluate the effects of CNS insults in order
to enable direct investigation of cerebral cellular events in the
human fetus and to relate cellular events to clinically observable
signs is an important research priority.  The methods must address
quantitation of severity of exposure, vulnerability of the fetus, and
the fetal response to the exposure.  Such tools would improve our
ability to diagnose fetuses and neonates who have and may continue to
sustain brain injury in utero.  Understanding of the temporal and
pathophysiologic processes would allow identification of appropriate
candidates for neuroprotective or neuronal rescue strategies and
would facilitate development of preventive strategies.

Scientific evidence supports the theory that some and possibly most
SIDS infants are born vulnerable to sudden death in infancy due to
chronic insults in utero.  Detailed pathologic studies of the central
nervous system of SIDS infants reveal abnormalities in regions that
control respiratory organs, arousal from sleep, and the activation
and control of cardiac function and breathing during sleep.  The
nature of the altered morphologies, i.e., abundance of dendritic
spines and hypomyelination, suggest that the maturation of these
regions is impaired in utero and early postnatal life.  Recordings of
heart rate and respiration of SIDS infants within the first weeks of
life show that the variation of their heart rate in response to
physiologic stimuli, such as breathing and blood pressure changes, or
in adaptation to behavioral state (sleep/waking) is limited.  These
findings also suggest central autonomic nervous system immaturity or
developmental disease.  In addition, infants shown to be at risk from
epidemiologic studies, such as infants experiencing an apparent
life-threatening event (ALTE), premature infants, or a sibling of a
SIDS infant, have been shown to have abnormal state dependent
autonomic responses to stimuli such as hypoxia, hypercarbia, and
temperature.  The physiologic deficits observed in recordings of
infants who later die or are at epidemiologic risk do not have the
specificity to be used as screening tools.

It would be a major step forward for clinicians and the research
community if screening tools could be developed that would define
abnormal neurologic development and/or intrauterine neurologic insult
in the fetus and/or neonate that was associated with a significant
risk of dying later in infancy, suddenly, and unexpectedly.

Other

The types of research approaches being sought by this RFA include,
but are not restricted to:

1.  Studies in animals that model early, recurrent, and/or chronic
central nervous system influences/insults in utero and include
assessments of central nervous system integrity in the fetus and
neonate.  Animal models must demonstrate relevance to the human fetus
and neonate.  The models should link severity of outcome with the
nature of the insult (e.g., type, timing, duration, location).
Examples of insults of interest include but are not limited to:
hypoxia, hypoglycemia, hypovolemia, infectious agents, and exposure
to substances of abuse.

2.  Studies in human fetal and neonatal subpopulations suspected of
being exposed to recurrent and/or chronic insults in utero that
assess central nervous system integrity and link assessment with
outcome.

STUDY POPULATIONS

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

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 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 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
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
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
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; 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; and from the program staff listed under
INQUIRIES.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

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
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 Executive Boulevard, Room 5E03
Bethesda, MD  20892

Applications must be received by April 29, 1994.  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 announcement 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 already reviewed, but such applications must include an
introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the Division of Scientific Review, National
Institute of Child Health and Human Development (NICHD) and the
National Institute of Neurological Disorders and Stroke (NINDS).
Incomplete applications will be returned to the applicant without
further consideration.  If the application is not responsive to the
RFA, NICHD and NINDS 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.

The review criteria to be used are identified below.  The NIH will
administratively withdraw from competition those applications judged
to be noncompetitive , and notify the applicant and institutional
business official. Those applications judged to competitive will
undergo further scientific merit review.  The second level of review
will be provided by the National Advisory Child Health and Human
Development and National Advisory Neurological Disorders and Stroke
Councils.

Review criteria for this RFA are generally the same as those for
unsolicited research grant applications.

o  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 the resources necessary to perform the research;

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

AWARD CRITERIA

The earliest anticipated date of award is September 30,1994.

Responsiveness to the RFA, scientific merit, and technical
proficiency, as described in the application, will be predominant
criteria for determining funding.

Assignment

For the purposes of this RFA:

Applications relevant to Sudden Infant Death Syndrome will have
primary assignment to the National Institute of Child Health and
Human Development.  Applications to further delineate the
pathogenesis of fetal brain injury will have primary assignment for
the purposes of this RFA to the National Institute of Neurologic
Disorders and Stroke.  Applications regarding the development of
diagnostics to identify infants who could benefit from neonatal
therapeutic strategies to prevent initiation or progression to brain
injury will have primary assignment to either the National Institute
of Child Health and Human Development or the National Institute of
Neurological Disorders and Stroke.

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:

Marian Willinger, Ph.D. or Linda Wright, M.D.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B03
Bethesda, MD  20892
Telephone:  (301) 496-5575

Giovanna Spinella, M.D.
Division of Convulsive, Developmental and Neuromuscular Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 8C-10
Bethesda, MD  20892
Telephone:  (301) 496-5821

Direct inquiries regarding fiscal matters to:

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

Mr. King P. Bond Jr.
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 10004
Bethesda, MD  20892
Telephone:  (301) 496-9231

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.365 (Research for Mothers and Children), and No.
93.853, Clinical Research Related to Neurological Disorders and
93.854, Biological Basic Research in the Neurosciences.  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.

.

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