Full Text HD-97-002
NIH GUIDE, Volume 26, Number 11, April 4, 1997
RFA:  HD-97-002
P.T. 34

  Biology, Cellular 
  Biology, Molecular 

National Institute of Child Health and Human Development
Application Receipt Date:  June 10, 1997
The National Institute of Child Health and Human Development (NICHD)
of the National Institutes of Health (NIH) invites innovative and
hypothesis-driven basic research project grant (R01 and R29)
applications designed to study the ontogeny of immunity and host
defense mechanisms in the fetus, neonate and infant.  The primary
objectives are to promote research to study the:  1) cellular,
molecular and genetic elements and mechanisms responsible for the
ontogeny of host defenses; 2) developmental biology of host defense
mechanisms in response to perinatal and postnatal infections; 3) key
cells, cytokines, cytokine-receptors, their interactions, and signal
transduction events involved in perinatal and postnatal host defense;
4) role, function, mechanisms and interactions of maternal
transplacental and colostral transfer of specific immunity on the
development and responsiveness of perinatal host defenses; and 5)
abnormal host defenses in early development that result in infant
morbidity and/or mortality.  Of particular interest are applications
studying the development of basic perinatal host defense mechanisms
in humans and non-human primates.
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), Ontogeny of Perinatal Host Defenses, is
related to the priority areas of maternal and infant health, and
immunization and infectious 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 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) award.  Racial/ethnic
minority individuals, women, and persons with disabilities are
encouraged to apply as Principal Investigators.
Competing continuation applications for already funded projects will
NOT be eligible for awards from NICHD under this RFA.
The mechanisms of support will be the individual research project
grant (R01) and FIRST (R29) awards.  Applications for FIRST Awards
and R01s from new investigators are particularly encouraged.  The
total project period for R29 applications is five years.  R01
applications submitted in response to this RFA may not exceed four
years; foreign applications may not request more than three years of
support.  The applicant will be responsible for planning, directing
and executing the proposed project.  The anticipated award date is
September 30, 1997.
This RFA is a one-time solicitation.  Future competing renewal
applications will compete with all unsolicited investigator-initiated
applications and will be reviewed according to standard NIH peer
review procedures.
The estimated funds available for the total (direct and facilities
and administrative) first-year costs of all awards made under this
RFA will be $1,500,000.  It is anticipated that the NICHD will award
up to eight R01/R29 grants for fiscal year 1997.  The awards and
level of support depend on receipt of a sufficient number of
applications of high scientific merit.  The usual PHS policies
governing grants administration and management, including facilities
and administrative (F & A) costs, will apply.  Although this
initiative is provided for in the financial plans of the NICHD,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.  Funding beyond the first and subsequent
years of the grant will be contingent upon satisfactory progress
during the preceding years and availability of funds.
The Center for Research for Mothers and Children (CRMC) of the NICHD
supports basic, translational and clinical research on maternal/child
health; pregnancy and parturition; normal and abnormal embryonic,
fetal and perinatal development; reproductive and developmental
immunology; congenital, perinatal and postnatal infections; Sudden
Infant Death Syndrome (SIDS); and therapeutic and prevention
strategies to reduce infant morbidity and mortality.  The
Developmental Biology, Genetics and Teratology Branch, and Pregnancy
and Perinatology Branch of the CRMC are particularly interested in
supporting basic studies on the ontogeny of perinatal host defenses
and developmental and reproductive immunobiology.  The goal of these
basic studies is to provide important fundamental knowledge,
understanding and insights that will translate into safe and
efficacious perinatal prophylactic and therapeutic modalities, as
well as useful prevention strategies to reduce infant morbidity and
Host defense mechanisms that protect the fetus, neonate and infant
are varied, complex and interactive.  Host genetic and environmental
factors appear to play an important role in the development of host
defenses.  Non-specific, natural or innate host defense mechanisms
include physical and chemical barriers; humoral components (e.g.,
serum opsonins, complement factors, fibronectin, c-reactive proteins,
and lactoferrin); natural killer (NK) cells; phagocytic cells (e.g.,
neutrophils, monocytes, macrophages); as well as soluble plasma and
tissue proteins that amplify the action of phagocytes to become
natural immune effector cells. Specific, adaptive or acquired host
defense mechanisms are comprised primarily of cell-mediated (T
lymphocyte) and humoral (B lymphocyte and immunoglobulin) systems.
Both non-specific and specific immune mechanisms are essential for
immunocompetence of the host.  Moreover, they are interdependent and
intimately related.  For example, monocytes and macrophages are
important components of both non-specific and specific immune defense
mechanisms. Macrophages act not only as important effector cells in
the expression of non-specific immunity; they also act as
antigen-processing and presenting cells that play a critical role in
triggering specific immunity mediated by B and T lymphocytes.
In recent years, our knowledge and understanding of human adult and
rodent immunology and host defense mechanisms have advanced rapidly
and significantly.  This has been made possible by the rapid and
revolutionary advances in biochemical, cellular, molecular, genetic
and transgenic technologies.  Nevertheless, large gaps in basic
developmental immunobiology and the molecular mechanisms of host
defenses in perinatal and postnatal humans and primates still remain
and need to be addressed.  These gaps cannot always be extrapolated
from adult human or rodent studies. For example, although the immune
system of the full-term human fetus is almost functionally mature, in
general it is not as efficient as the adult immune system.  There are
definite functional differences between the adult and neonatal immune
systems.  At birth the neonatal B and T lymphocytes are generally
naive and unprimed, so they have not undergone antigen-induced clonal
expansion or maturation.  This partially accounts for the human
neonate's susceptibility to infection.  Although neonatal B
lymphocytes are mature and functional, they are unable to produce
some specialized antibodies such as IgA and IgG2 against some types
of encapsulated bacteria.  The neonatal T lymphocyte repertoire is
somewhat functionally immature compared to adult T lymphocytes.
Important functional differences in neonatal T lymphocytes include
diminished capacity to provide help for or actual suppression of
immunoglobulin production by B lymphocytes, diminished generation and
activity of cytotoxic T lymphocytes, and decreased capacity to
activate macrophages.  Neonatal T lymphocytes also have a markedly
diminished capacity to produce certain cytokines (e.g., IFN-gamma and
IL-4). Recent studies indicate that antigenic naivete is the
principal mechanism for selective lymphokine deficiency in neonates.
It is clear that additional studies targeted to perinatal humans and
primates, as well as relevant animal models, need to be conducted to
fully elucidate and understand the ontogeny and mechanisms of
perinatal host defenses.
Other areas which require additional research are the role,
mechanisms and interactions of maternal immunity in perinatal host
immune defenses.  This is especially important in humans and
primates, where the molecular mechanisms and impact of perinatal
transplacental and colostral transfer of specific immunity need
better understanding.
Clearly, a better knowledge and understanding of perinatal host
defenses and maternal immune interactions have important clinical
implications.  Perinatal host defenses are not identical to adult
host defenses.  Fetuses and neonates are generally less capable of
coping with perinatal infections.  For example, primary HIV-1, herpes
virus, and toxoplasma infections in a fetus are usually more severe
and aggressive than in an adult.  Thus, some of the parameters and
criteria for diagnosing, staging and treating perinatal infections
are different compared to an adult.  A knowledge of the temporal
development of immunity and perinatal host defense mechanisms is thus
clinically important for treatment of congenital and perinatal
infections. Understanding the sequential development of host immune
defenses is also crucial for developing and administering vaccines.
The timing for immunization should be based on a thorough and
rational understanding of the ontogeny and sequential development of
immunity.  This would maximize the specificity, level and duration of
immunologic protection. In recent years, modern advances in neonatal
intensive care units have increased the survivability of premature
and low birth weight babies.  This new group of babies is generally
not sufficiently developed to cope with the extrauterine environment
without assistance.  Their immaturity predisposes them to a multitude
of problems, including pulmonary viral infections.  Moreover, their
underdeveloped immune system and host defenses severely compromise
their ability to produce antibodies and mount a protective and
specific host immune response.  These preterm babies also tend to
have lower maternal IgG levels compared to term babies.  This leaves
them vulnerable to the detrimental effects of many infectious agents.
In these premature babies, it is essential to find effective means of
enhancing or accelerating the development of their host immune
defenses.  This requires a basic understanding of how and when the
components of the immune system and host defenses develop as well as
the key cellular, molecular and genetic elements and mechanisms that
drive their sequential development.
Finally, the relationship of SIDS to the developing immune system and
host defense response to infection needs further exploration.
Several studies suggest that mild respiratory or gastrointestinal
tract infections are predisposing factors in infants who succumb to
SIDS.  A few studies implicate toxigenic bacteria as etiologic
agents.  Other reports suggest that abnormal immune responses such as
hypersecretion of immunoglobulins in the respiratory tract, elevated
interleukins, or anaphylaxis play a role in SIDS pathogenesis.  Thus
it is important to understand how abnormal or delayed development of
host immune defenses contribute to SIDS.
The recent advances in molecular biology and genetics provide new
opportunities, insights and technologies for studying the development
of the immune system and perinatal host defense mechanisms.  The
temporal expression of important developmental genes and the actions
and interactions of their gene products (e.g. cytokines) can now be
studied.  This makes it feasible to molecularly and biologically
dissect and characterize the key elements, mechanisms and signal
transduction pathways that are important in the ontogeny of host
immune defense mechanisms. It also provides critical information for
developing new approaches and biotechnologic and pharmaceutic
products either for enhancing positive or blocking adverse host
defense mechanisms in vivo.
This RFA was developed primarily to address the large gaps in our
basic knowledge and understanding of the developing immune system and
perinatal host defenses in humans and primates.  It was also
stimulated by the 1996 Report of the NIH AIDS Research Program
Evaluation Working Group. Although the report focused on AIDS, it
also addressed the critical need for high-quality, novel or
innovative, investigator-initiated, basic research studies to better
understand the human and primate immune systems. Furthermore, it
strongly encouraged increasing research support for selected
understudied and underfunded areas of basic human immunobiology and
physiology, and the development of host defense mechanisms against
infection in the neonate.  New knowledge in these areas would greatly
benefit our understanding of pediatric AIDS and translate into
effective prophylactic, therapeutic and prevention strategies.  The
work group described important gaps in our basic knowledge of the
immune system, but it also revealed promising new opportunities,
insights and approaches for future research.
Research Scope
The objective of this RFA is to encourage and promote innovative and
hypothesis-driven basic research projects, primarily in humans and
primates, but also in relevant animal models, to study the ontogeny
of specific or acquired perinatal host defense mechanisms; the
sequential acquisition of antigen-specific perinatal cell-mediated
and antibody-mediated immune responses; and the major differences
between perinatal and adult immunity and host defenses.  This RFA is
for applications focused primarily on the ontogeny and host defense
mechanisms of perinatal and postnatal T lymphocytes, B lymphocytes,
immunoglobulins, monocytes, macrophages, NK cells and their
associated specific humoral components.  Studies which address the
role and mechanisms of transplacentally and colostrally acquired
specific humoral and cellular elements on perinatal host defense are
appropriate for this RFA.  Studies on perinatal neutrophils, natural
humoral factors (such as opsonins, complement, fibronectin,
C-reactive protein and lactoferrin) and non-specific substances in
breast milk are beyond the scope of this RFA.  Applications on these
latter topics will be considered non-responsive and returned to the
The research scope includes basic studies listed in the PURPOSE
section of this RFA.  The following are examples of research topics
that are appropriate for this RFA; however, they are not to be
considered as exclusive or limiting:
o  Identify and characterize genes encoding specific proteins
essential for the ontogeny of immunity and host defenses.
o  Elucidate the biochemical, cellular, molecular and genetic
elements and mechanisms responsible for the development of host
defenses during perinatal infections.
o  Identify specific cytokines, their receptors and transcription
factors, and define their role in development of perinatal host
defense mechanisms.
o  Identify and characterize the genes and their protein products
involved in cytokine-receptor signaling pathways; elucidate the
molecular mechanisms of signal transduction and pathways that are
important for development and responsiveness of host defenses.
o  Identify MHC genes and their products that are important in the
ontogeny of perinatal host defenses; determine the mechanisms of
class I and class II HLA antigens in the induction and expression of
perinatal cellular and humoral immunity.
o  Elucidate how specific congenital or perinatal infections may
impair or delay the development of perinatal host defenses.
o  Determine how inherited and acquired immunodeficiencies may
compromise the ontogeny of perinatal host immune defenses.
o  Elucidate the molecular mechanisms involved in transplacental and
colostral transfer of specific immunity to the fetus and neonate.
o  Study the host genetic and environmental factors which affect the
ontogeny of host defenses.
o  Characterize the molecular and cellular basis of immune
recognition of perinatal infectious agents; determine the role and
ontogeny of specific host defenses; and define the molecular basis
for perinatal T cell receptor diversity and immunogenetic regulation
of specific T cell responses.
o  Develop primate and other animal models that will be useful for
understanding the basic development of perinatal host defenses and
responsiveness to infection.
o  Develop and use appropriate transgenic mouse models to identify
and elucidate important molecular genetic mechanisms responsible for
ontogeny of perinatal host defenses.
o  Determine the role of host immune responses in the pathogenesis of
The areas of interest listed above are not in any order of priority.
They are only suggested examples of areas of research to consider.
Applicants are encouraged to propose other areas that are related to
the objectives and scope of this RFA.
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification are
provided that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
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 the NIH
Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95).  Applications kits are available at most
institutional offices of sponsored research and may be obtained from
the Division of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, email:
ASKNIH@odrockm1.od.nih.gov; and from the NICHD program administrator
listed under INQUIRIES.
Since a letter of intent is not solicited or required, applicants are
strongly encouraged to contact NICHD program staff listed under
INQUIRIES in the early stages of preparing the application.
For all applications, 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 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, and three signed photocopies in one package to:
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)
At the time of submission, two additional copies of the application
must also be sent or delivered under separate cover to:
Susan Streufert, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03 - MSC-7510
Bethesda, MD  20892-7510
Rockville, MD  20852-7510 (for express/courier service)
Telephone:  (301) 496-1485
FAX:  (301) 402-4104
Email:  StreufeS@HD01.nichd.nih.gov
Applications prepared in response to this RFA must be received by
June 10, 1997.  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 the
same as one already reviewed.  This does not preclude submission of a
substantially revised application already reviewed, but such an
application must include an introduction addressing the previous
FIRST (R29) applications must include at least three sealed letters
of reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
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 could be included
with the application.
Applications for the FIRST (R29) award must comply with the NIH
Guidelines for FIRST awards and the Just-in-Time procedures announced
in the NIH Guide, Vol. 25, No. 10, March 29, 1996.
Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness by the NICHD.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, DRG staff may 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.  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 NICHD in accordance with the review criteria stated below.
As part of the initial merit review, a process 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, assigned a
priority score, and receive a second level of review by the National
Advisory Child Health and Human Development (NACHHD) Council.
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.  A summary
statement will be prepared for non-competitive applications.
Review Criteria
Review criteria for this RFA are generally the same as those for
unsolicited NIH research project grant applications.
o  scientific, technical, or medical significance and originality of
proposed research;
o  appropriateness, feasibility and adequacy of the experimental
approach and methodology proposed to carry out the research;
o  qualifications, competence 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 and facilities necessary to perform
the research;
o  appropriateness of the proposed budget and duration in relation to
the proposed research;
o for research involving human subjects, 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.
The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.  Furthermore, it will consider and evaluate how
the proposed research would advance the goals targeted in this RFA.
The anticipated date of award is September 30, 1997. Applications
recommended by the NACHHD Council will be considered for awards.
Awards will be based on the scientific merit of the proposed project
as determined by peer review, program priorities and balance of
research areas targeted in the RFA, and availability of funds.
Written, telephone and email inquiries concerning this RFA are
strongly encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
Direct programmatic inquiries to:
Allan Lock, D.V.M.
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B01 - MSC-7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-5541
FAX:  (301) 402-4083
Email:  LockA@hd01.nichd.nih.gov
Direct fiscal inquiries to:
Mr. E. Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17 - MSC-7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  ShawverD@hd01.nichd.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.865 - Research for Mothers and Children. 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.
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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