Full Text HD-94-004


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

RFA:  HD-94-004

P.T. 34

  Human Reproduction/Fertility 
  Physiology, Human 

National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  July 26, 1993
Application Receipt Date:  September 8, 1993


The National Institute of Child Health and Human Development (NICHD)
invites research grant applications for the support of studies of the
genetics and physiology of human oocytes that may lead to improvements
in the alleviation of infertility or the acquisition of a better
understanding of mechanisms regulating fertility that may lead to new
approaches to contraception.  An important part of the mission of the
NICHD is to gain new knowledge about human reproduction and this
Request for Applications (RFA) is intended to address that charge.


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,
Genetics and Physiology of Human Oocytes, is related to the priority
area of family planning.  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 domestic and foreign for-profit and
non-profit organizations, public and private.  Minority individuals,
persons with disabilities, and women are encouraged to apply.


This RFA will use the NIH individual research project grant (R01).
Responsibility for the planning, direction and execution of the
proposed project will be solely that of the applicant.  The total
project period for applications submitted in response to the present
RFA may not exceed five years.  The earliest expected award date is
April 1, 1994.

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.  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.  It is anticipated that most of the awards will
go to new applications but competing renewal applications for an
ongoing research project may be submitted in response to this RFA.


It is expected that up to four new applications will be funded, within
the direct cost limit of $800,000 available for the first year.  This
level of support 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 NICHD, awards pursuant to
this RFA are contingent upon the availability of funds for this


The overall goal of this RFA is to stimulate and support research on
the gain of knowledge of genetic and physiological regulatory
mechanisms in human oocytes.  The motivation to learn more about the
basic biology of human oocytes is that they are of enormous scientific
and medical importance; there are demonstrable needs for this
information; there is availability of human oocytes through current
medical procedures; and there are dramatic new technological advances
that can be applied to human oocytes.  Among the most pressing needs
are: (1) the need for improved methods to alleviate infertility and to
understand the causes of infertility, (2) the need for new
contraceptive leads that are effective before fertilization, (3) the
need for improved genetic analysis before fertilization, and (4) in the
support of the above three needs, the need to assess the quality of an
individual human oocyte in the context of its potential for
fertilization and development into a healthy offspring.  Beneficiaries
of this initiative will be those who are interested in the various
problems represented by the needs given above, such as infertility,
contraception, environmental, aging and disease effects upon female
germ cells, birth defects, as well as the fundamental developmental
biology of human oocytes.  Despite this display of profound needs and
numerous beneficiaries, our scientific knowledge of the human oocyte is
negligible at a time when our current molecular genetic and cell
physiological techniques are of such high resolution that they can be
applied to single cells, such as oocytes.

The results of studies generated by this RFA are expected to
substantially advance our knowledge base of the genetic and
physiological mechanisms that regulate the developmental program of
human oocyte maturation.  There is much evidence that substantial
differences exist among the species for a number of experimental and
observational parameters, such that increased knowledge about human
oocytes must be obtained directly through experiments and observations
on human oocytes.

Even with our present, rapidly improving technology, there are many
unanswered questions about mammalian reproduction owing partly to the
complexity of mammalian reproduction and to the difficulty in doing
experiments on the relatively small numbers of mammalian oocytes.  The
complexity of reproduction in humans is magnified owing to the long
fertile period for both males and females.  Indeed, it is of great
importance to better understand the reasons for the unusually high
incidence of infertility in humans compared with other mammals.  It has
been estimated that as many as 60 percent of human fertilized eggs do
not develop into a live offspring under normal conditions, owing to
immunological causes, chromosome or genetic abnormalities, and other
physiological causes.  Some of this failure is likely to be due to the
estimated 30 percent of ovulated human eggs that have obvious
chromosomal abnormalities.  There is also the complication that, for
many purposes and reasons, mammalian oocytes and embryos must be
studied as single eggs or embryos.  Now, the recent development and
refinement of a number of cell physiological and molecular genetic
techniques that can be applied to single cells or embryos can be
applied to single human oocytes.  There have been recent dramatic
advances in our ability to culture oocytes of mice and other mammals.
Also, through a variety of medical procedures in common practice, there
is availability of sufficient human oocytes that would otherwise be
discarded.  Thus, it is evident that the need, the availability and the
technology exist for high resolution studies on single human oocytes.
The end result is expected to be a greatly increased ability to obtain,
identify and characterize high quality human oocytes.

Three recent NIH conferences and a detailed Institute of Medicine study
have emphasized the dramatic new advances in mammalian oocyte culture
systems and the rapidly advancing high resolution technologies for cell
physiological and molecular genetic analysis of single mammalian
oocytes.  At the same meetings, discussions were held of the future
research needs in the field of mammalian gametogenesis and other areas
of reproduction.  Among these was a need for application of these
recent advances to human oocytes.  The conferences and study were
October 1991, "Meiosis II: Contemporary Approaches;" February 1992,
"Opportunities in Contraception: Research and Development;" May 1992,
"Physiology of Mammalian Oocytes and Preimplantation Embryos;" 1989,
"Medically Assisted Conception," (National Academy Press).

It should be noted that the use of federal funds for research on human
in vitro fertilization presently requires the review, prior to award,
by an authorized Ethics Advisory Board.


Owing to the recognition that the key endpoint of experiments on human
oocytes will be the production of high quality eggs, a principal, but
not exclusive, target of this RFA is to study oocyte maturation in
which the oocyte undergoes germinal vesicle break down (GVBD), first
polar body release, and progression to metaphase of Meiosis II.  This
competence to mature can indicate that an egg is fertilizable and is
therefore a particularly important criterion for egg quality.  In
addition, successful maturation itself is a valuable endpoint for
studies conducted on earlier phases of oocyte growth and development.
In this context, studies of the development of preantral follicles
would be another principal target of this competition.  In general, the
entire range of genetic, molecular, and cell physiological assessments
of human oocytes would be within the research objectives of this RFA,
including approaches that would lead to improved culture conditions.
Noninvasive assessments or steps leading to the development of
noninvasive assessments of single human oocytes would be of particular
interest and importance to the goals of this RFA.

For the purpose of this RFA, genetics and physiology of human oocytes
would include, but not be limited to, the following topics that would
primarily focus upon oocytes in culture:

o  regulation of growth and differentiation of oocytes
o  regulation of meiosis
o  role of hormones in oocyte maturation in vitro
o  cytoplasmic and nuclear maturation
o  interaction between oocytes and surrounding somatic cells
o  culture of oocyte-cumulus complexes
o  regulation of oocyte cell cycle events

Experimental designs could include, but are not limited to, molecular,
genetic, cell physiological, biochemical, and nutritional approaches.
It is anticipated that some of these approaches would include
high-resolution, noninvasive methods to assess the quality or condition
of single human oocytes.



NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are 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 must be placed on the need for inclusion of minorities in
studies of diseases, disorders and conditions which disproportionately
affect them.  If 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 racial/ethnic group.  In addition, 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

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,

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 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.


Prospective applicants are strongly encouraged, but not required, to
submit, by July 26, 1993, 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 allows NICHD staff to estimate the potential review
workload and to avoid conflict of interest circumstances in the review

The letter of intent is to be sent to Dr. Richard J. Tasca at the
address listed under INQUIRIES.


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, Westwood Building, Room 449, Bethesda, MD 20892, telephone

The RFA label available in the PHS 398 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 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 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.  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.


Upon receipt, applications will be reviewed by NICHD staff for
completeness and responsiveness.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, it will be returned to the
applicant, who may then submit it to DRG for review in competition with
unsolicited applications at the next available review cycle.

Responsive applications may be triaged by a peer review group to
determine their relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be noncompetitive for
award and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further evaluation for scientific merit.  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 NICHD.  The second level of review
will be provided by the National Advisory Child Health and Human
Development (NACHHD) Council.

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications, including:

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, and of collaborators, if applicable;

o  adequacy of time and effort dedicated to the project;

o  availability of the resources necessary to perform the research;

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


The earliest anticipated date of the award is April 1, 1994.  Funding
decisions will be based upon peer review and NACHHD Council
recommendations, program relevance, and availability of funds.


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 scientific issues and address the letter of
intent to:

Richard J. Tasca, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01
Bethesda, MD  20892
Telephone:  (301) 496-6515
FAX:  (301) 496-0962

Direct inquiries regarding fiscal matters to:

Melinda Nelson
Office of Grants and Contracts
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B17
Bethesda, MD  20892
Telephone:  (301) 496-5481


This program is described in the Catalog of Federal Domestic Assistance
No. 93.864, Population Research.  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 12374 or Health Systems Agency review.


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