Subject: NIH GUIDE - Vol. 20, No. 10, March 8, 1991 - RFA HD9110
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Fri, 08 Mar 91 09:54 EST

Hi,
 #10  Please post to the listserver as: RFAHD-91-10.910308
       Dottie
 ---------------------------- Text of forwarded message -----------------------
 
$$XID RFA HD9110 HD-91-10 P1O1 *****************************************
 
REQUEST FOR RESEARCH APPLICATIONS
 
RFA:  HD-91-10
 
EFFECT OF SPECIFIC COMPONENTS OF HUMAN MILK ON THE NURSLING
 
P.T. 34; K.W. 0750015, 0775015, 1003008, 0760020, 0760025
 
National Institute of Child Health and Human Development
 
Application Receipt Date:  July 24, 1991
 
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, Effect
of Specific Components of Human Milk on the Nursling, 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, D.C. 20402-9325 (telephone
202-783-3238).
 
The Endocrinology, Nutrition, and Growth Branch of the Center for
Research for Mothers and Children of the National Institute of Child
Health and Human Development (NICHD) invites research grant applications
on the effects of specific components of human milk on the nursing
infant with respect to nutrition, physiological maturation of specific
tissues or organ systems, and susceptibility to infection and
malignancies, endocrinopathies, and degenerative disorders.  Of
particular interest are studies designed to determine the mechanisms of
these effects.
 
BACKGROUND
 
Over the last twenty years we have become aware that human milk is a
complex mixture which contains many substances besides those which meet
the classical nutritional requirements of newborn infants.  Many of
these substances are not present in cow milk or infant formula or are
present there only in much lower concentrations.  They include enzymes,
hormones, growth factors, antibodies, specific proteins of other
classes, non-protein nitrogenous substances, and oligosaccharides.  Some
of these substances which are of large molecular size can nevertheless
be absorbed intact from the immature gastrointestinal tract.  Many of
them have powerful biological actions in other in vivo and in vitro
contexts, but for only a few have we learned the physiological import of
their presence in milk.  Whether the others have significant
developmental effects on the nursing infant or are only incidental
passengers of the milk secretion process is unknown.
 
It seems likely that hormones present in human milk at levels
several-fold greater than those in plasma, like somatostatin or growth
hormone, or five-fold greater, like oxytocin, or 20-90 times greater,
like calcitonin, have some effect on the nursing infant, but even those
hormones with low milk/plasma ratios may have functional significance in
milk.  In rats, prolactin ingested by the pups in milk is necessary for
the development of normal pituitary control over prolactin secretion in
later life.  Whether any of the other hormones of milk, which include
insulin, TRH, TSH, corticosteroids, estrogen, progesterone, EGF, NGF,
IGF 1 and 2, TGFs, erythropoietin, bombesin, neurotensin, VIP, and
prostaglandins, have any physiological significance to the infant
remains to be determined.
 
There are a number of other compounds which are present in much higher
concentrations in human milk than in formula.  These include small
molecules like lactoferrin, an iron chelator with putative antibacterial
or other immunologic properties, enzymes like bile salt-stimulated
lipase, lysozyme, and amylase, purine and pyrimidine nucleotides, and
secretory IgA.  There are also leukocytes, leukocyte migration factors,
and probably polysaccharides or glycoproteins which mimic intestinal
receptors for pathogenic organisms, binding to those organisms and
serving as a defense against infection.  There are unknown materials
which facilitate the absorption of iron and other elements and factor(s)
which stimulate the establishment of normal intestinal flora.
 
Many infants have been raised successfully on non-human milks.
Nevertheless, it is important to learn whether various components of
human milk affect development and maturation, not only for the basic
science information to be gained, but also for the potential benefit to
infants who do not receive beikost at an early age, as well as those who
must be maintained on parenteral nutrition, those who are suckled in
unsanitary environments, and those who are of low birth-weight.  Even
for normal infants in favorable surroundings there may be long-term
benefits from specific components of human milk, as suggested by
case-control studies of juvenile diabetes and childhood lymphoma.
 
It is difficult to do this kind of research in human infants, and
sometimes non-rigorous inferences must be drawn from research on animal
models.  Until recently taurine, which is the second most common amino
acid in human milk, was not present in any commercial infant formula.
However, because of evidence that taurine deficiency produces abnormal
electroretinographic responses in infant animals, and because a study in
low-birth-weight human infants suggested that they developed mature
auditory evoked responses more rapidly when given taurine, this
substance is now routinely added to all infant formulas.  As a result,
ethical considerations now forbid the intentional induction of taurine
deprivation in human babies, and studies of taurine function in the
newborn demand model systems.  Similarly, there is a delay in the
maturation of rod cells in the retina when premature infants are fed
formulas which differ from human milk by containing relatively low
levels of omega-3 fatty acids.  Because of this and because of
convincing animal studies on the effect of such fatty acids on
maturation of the visual system, the addition of linolenic acid to
formula intended for low-birth-weight infants is now mandated in Canada.
 
Although it is commonly stated that human milk is the optimal food for
newborn humans, it might be possible to develop artificial formulae
which enhance infant development and health even more than does human
milk, especially in situations where the infant is stressed, ill,
handicapped with congenital defects or inborn errors of metabolism, or
developmentally delayed.  The development of such formulas will depend
on knowledge of how specific components of human milk affect the
nursling.
 
RESEARCH GOALS
 
Most full-term infants thrive on artificial formulas which lack high
concentrations of the human milk-specific components.  Their development
apparently proceeds satisfactorily without any specific stimulation that
these substances may provide.  On the other hand, the maturation of
low-birth-weight infants proceeds less smoothly, and is complicated by
conditions such as the respiratory distress syndrome, bronchopulmonary
dysplasia, and necrotizing enterocolitis which seem to result from
maturational deficiencies.  An understanding of how human milk
components influence intestinal maturation, lung function, intellectual
development, specific or nonspecific immunity, or other variables in the
neonatal period could lead to specific therapeutic uses of these
components in undersized, developmentally delayed, or ill infants.
Studies of human milk components could also provide important, broadly
applicable information about their biological functions in general.
 
This RFA is issued to encourage investigators to undertake clinical
studies of the role of specific components of human milk in normal
development and disease resistance, and to develop animal or
organ/tissue models when studies in humans are impractical or unethical.
Nonclinical model studies must focus on the effects of components of
human milk.  Studies of these topics are expected to increase our
understanding of the physiologic role and pharmacologic potential of
human milk components, and to lead to improved formulas for artificially
fed infants.  This is an underinvestigated area of research on
maternal-infant interactions, with potentially important clinical
applications.
 
SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF
NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN
CLINICAL RESEARCH STUDY POPULATIONS
 
NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be 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
should 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 should 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 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 in Section 2, A-D of the Research
Plan AND summarized in Section 2, E, Human Subjects.
Applicants/offerors 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 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 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.
 
MECHANISM OF SUPPORT
 
Applications in response to this RFA will be funded through the
traditional individual research award (RO1) program of the NIH.  This
announcement is for a single competition with the application receipt
deadline of July 24, 1991.  The earliest possible start date for these
grants is March 1, 1992.  It is anticipated that four (4) grants will be
awarded under this program, contingent upon receipt of a sufficient
number of meritorious applications and the availability of funds.
$600,000 has been set aside for fund these awards.
 
REVIEW PROCEDURES AND CRITERIA
 
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.  If the
application submitted in response to this RFA is substantially similar
to a research 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.
 
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 group review convened solely for this
purpose by the Scientific Review Program, 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 Institute's Advisory Council for program relevance and policy issues
before awards for meritorious proposals are made.
 
APPLICATION PROCEDURE
 
Applications must be submitted on form PHS 398 (rev.  10/88), available
in business or grants offices at most academic research institutions or
from the Division of Research Grants, NIH.  The phrase RFA HD-91-10
EFFECT OF SPECIFIC COMPONENTS OF HUMAN MILK ON THE NURSLING must appear
in item 2 of the face page.  The RFA label available in the 10/88
version of form PHS 398 must be affixed to the bottom of the face page.
Failure to use this label could result in delayed processing of an
application, so that it may not reach the initial review group in time
for review.  The original and four (4) copies are to be sent no later
than July 24, 1991, to:
 
Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
 
In addition to the copies sent to the Division of Research Grants, two
(2) copies of the application should be sent to:
 
Laurance Johnston, Ph.D.
Scientific Review Program
National Institute of Child Health and Human Development
Executive Plaza North, Room 520A
Rockville, MD  20852
 
Any inquiries about this RFA should be directed to:
 
Ephraim Y. Levin, M.D.
Medical Officer, Endocrinology, Nutrition and Growth Branch
Center for Research for Mothers and Children
National Institute of Child Health and Human Development
Executive Plaza North, Room 637
Rockville, MD  20852
Telephone:  (30l) 496-5593
 
For fiscal and administrative matters, contact:
 
Mr. E. Douglas Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
Executive Plaza North, Room 501
Rockville, MD  20852
Telephone:  (301) 496-1303
 
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 grant 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.