Full Text HD-97-004
NIH GUIDE, Volume 26, Number 14, May 2, 1997
RFA:  HD-97-004
P.T. 34

  Human Reproduction/Fertility 

National Institute of Child Health and Human Development
Letter of Intent Receipt Date: May 30, 1997
Application Receipt Date:  June 13, 1997
The National Institute of Child Health and Human Development (NICHD)
invites research project grant (R01) applications for the support of
studies of male germ cell growth and differentiation.  The
establishment of effective culture systems for male germ cells is a
prerequisite to obtaining a better understanding of the developmental
mechanisms by which male germ cells develop into mature sperm cells.
The lack of such culture systems has greatly hindered progress
towards this understanding.  One particular goal of this initiative
is to improve our ability to culture the self-renewable
spermatogonial stem cells in order to be able to conduct cause and
effect experiments.  It may also be possible to establish lines of
these potentially immortal stem cells.  These advances, coupled with
a recent breakthrough in our ability to transplant these cells into
the testes of infertile mice would establish a test system for the
assessment of the developmental potential of the cultured and
transplanted spermatogenic cells.  This system also would provide the
opportunity to study ways to genetically alter male germ cells such
that these alterations can be passed on to the next generation
through mature sperm and fertilization.  It is expected that the new
knowledge derived from these studies will lead to the alleviation of
certain forms of male infertility and to the discovery of novel
contraceptive approaches as well as to a wide array of other
potential benefits.  An important part of the mission of NICHD is to
gain new knowledge about human reproduction and this Request for
Applications (RFA) is designed to address that mission.
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,
Male Germ Cell Growth and Differentiation, 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
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.
Racial/ethnic minority individuals, women and persons with
disabilities are encouraged to apply as Principal Investigators.
The funding mechanism to be used to assist the scientific community
in achieving the objectives of this RFA will be the National
Institutes of Health (NIH) 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 an application submitted in response to this RFA
may not exceed five years. The earliest expected award date is
December 1, 1997.
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.  New applications, as well as
competing renewal applications for an ongoing research project, may
be submitted in response to this RFA.
Although this solicitation is included in the NICHD plans, support
for these grants is contingent upon the availability of funds for
this purpose.  The number of grants to be awarded is also contingent
upon a sufficient number of applications deemed meritorious enough to
be considered for an award.  It is anticipated that an estimated
total cost of $540,000 will be available for the first year to
support approximately three grants.  Because the nature and scope of
the research proposed in response to this RFA may vary, it is
anticipated that the size of the awards will also vary within the
funding limits available.
It is estimated that as many as 10% of reproductive age couples in
the United States are infertile.  Within this context, approximately
40% of human infertility cases are correlated with disorders in the
male.  We also recognize that there have been pills and other
contraceptive methods available for female contraception for many
years, but male contraceptive methods have been limited mostly to
vasectomies and condoms.  This should not be surprising since our
knowledge of the process of spermatogenesis is negligible.  New
technologies and motivations now exist that could improve this
knowledge.  With this improved knowledge, it should be possible to
greatly increase our ability to regulate male reproduction and to
address these two issues of male infertility and male-side
contraception, using new modes of diagnosis and therapy as well as
providing additional contraceptive choices.
Accordingly, the purpose of this RFA is to stimulate and encourage
the development of culture systems for spermatogonial stem cells, the
most immature, yet completely self-renewable, germ cells in the
testis.  These cells undergo growth, meiosis and differentiation in
their development into mature sperm cells.  However, the male and
female gametes of mammals develop internally from spermatogonial and
oogonial stem cells in the testis and ovary, respectively.  Likewise,
mammalian fertilization is internal and the various stages of
embryonic development also occur internally so that it is difficult
to observe these processes as they occur naturally.  For egg
development, as well as fertilization and early embryo development,
culture systems have now been devised that allow one to observe and
to conduct experiments and then to test the developmental potency of
the oocyte or fertilized egg or early embryo by placing them back
into the female reproductive tract for further development.  These
culture systems are still far from ideal, but they do permit
considerable experimental manipulations to be done and cause and
effect conclusions to be made.  However, our ability to culture male
germ cells is severely limited to brief and disconnected periods
during the transition from spermatogonial stem cells to mature sperm.
Thus, we have a very poor understanding of the mechanisms that
control the development of spermatogonial stem cells into mature
A recent breakthrough in male reproduction was the successful
transplantation of spermatogonial stem cells from one testis to an
infertile testis of the same or a different species and the ability
to cryopreserve these spermatogonial stem cells prior to
transplantation.  The transplanted stem cells were able to undergo
apparently normal spermatogenesis.  This, then, established an in
vivo system for assessment of the developmental potency of male germ
cells after various in vivo or in vitro treatments, that might
include production of cell lines with specific genetic alterations.
With this technology, it will now be possible to test the in vivo
developmental potential of stem cells that have developed in vitro.
This opportunity to conduct rigorous in vivo tests of the
developmental potential of male germ cells produced in this manner
fills in one of the key voids in the technical armamentarium for male
reproduction.  This technology will be necessary in order to make
rapid progress towards improved scientific understanding of male
reproduction and towards practical applications that will have broad
benefits to human health.
Some of the benefits to human health that may be derived from
increased knowledge of spermatogenesis through culture system
improvements for spermatogonial stem cells include 1) major new
insights into the genetic and other causes of certain types of male
infertility that could lead to 2) development of effective points of
alleviation of this infertility through assisted reproductive
technologies, 3) discovery of novel contraceptive approaches, 4) the
possibility that defective genes can be corrected in spermatogonial
stem cell lines that can then be used therapeutically to eliminate
certain devastating genetic diseases, 5) a vastly enhanced
opportunity to understand how stem cells work in general since the
spermatogonial stem cell population has the property of self-renewal,
and 6) provide an additional method to generate transgenic animals as
models of human diseases and disorders that may have certain
advantages over the egg microinjection and the embryonic stem cell
There have been several recent NIH conferences and workshops and a
detailed Institute of Medicine study that clarified the need for
enhanced support of research in the area of this RFA.  The
conferences were 1) October 1991, "Meiosis II:  Contemporary
Approaches to the Study of Meiosis," 2) February 1992, "Opportunities
in Contraception:  Research and Development," 3) March 1993, "A New
Look at Spermatogenesis," 4) August 1994, "Male Infertility and
Impotence:  Current Perspectives and New Directions for Basic and
Clinical Research," 5) November 1994, "The Germ Line," and 6) May
1996, "Workshop on Transgenic Mouse Sperm Cryopreservation."  The
Institute of Medicine Report published in 1996 by the National
Academy Press is on "Contraceptive Research and Development:  Looking
to the Future," and was based largely upon the "Workshop on
Contraceptive Research and Development and the Frontiers of
Contemporary Science," that was held in December, 1994 at the
National Academy of Sciences.  Much of the research reported and
discussed at these meetings revealed a massive increase in molecular
genetic approaches that could be applied to male reproduction.  It
was clear from these meetings that full advantage of this modern
technology could not be currently applied to testicular germ cells
owing to the unavailability of culture systems for these cells.
The principal objective of this RFA is to stimulate and encourage the
development of culture systems for spermatogonial stem cells.  Our
knowledge of the mechanisms by which spermatogonial stem cells
develop into mature sperm is negligible.  In order to fill this void
in our knowledge it is imperative that we be able to conduct
experimentation and make detailed observations of the various phases
of spermatogenesis that include cell proliferation, meiosis and
spermiogenesis.  Meeting this principal objective is expected to help
to improve our basic knowledge of sperm development and to rapidly
advance our ability to apply this knowledge to key aspects of the
mission of NICHD in alleviating infertility and in discovering novel
contraceptive leads.
In order to create a satisfactory culture system for this objective,
it will be necessary to be able to obtain, identify and characterize
high quality spermatogonial stem cells.  These will be spermatogonia
that are capable of self-renewal.  Primary culture systems for these
spermatogonial stem cells could be established that would allow for
cell replication and observations and testing. The establishment of
stable tissue culture lines of these spermatogonial stem cells would
vastly facilitate reaching the objectives of this research, for these
could then be used as a starting point for development of full in
vitro or in vivo development of spermatogenic cells through the
formation of mature sperm.  The spermatogonial stem cell lines could
be genetically altered, and then sperm could be used to carry altered
genes into the next generation.  While there has been considerable
success in obtaining highly purified yields of these spermatogonial
stem cells from mouse and rat testes, there is still much work to be
done in identifying and characterizing them.  The determination that
they are of high quality can only be accomplished by showing that
they have full developmental potential to develop into mature sperm
that are capable of fertilizing an egg and resulting in healthy
offspring.  Currently, this latter aspect of the research can be done
through transplantation of spermatogonial stem cells into infertile
testes, where development has been shown to proceed through
spermatogenesis and result in mature sperm.  This procedure is
presently inefficient, however, and improving the efficiency is a
necessary part of the objectives of this RFA.  It may be that a more
favorable genetically or chemically-induced infertile testis model
may be selected or developed that would provide better efficiency
than those that have been used to date.
Research Scope
For this RFA, an application could focus upon, but would not be
limited to, any of the following:
o improvements in the isolation, identification, characterization and
culture of spermatogonial stem cells of mammals o improvements in the
ability to culture spermatogonial stem cells in such a way as to
maintain their developmental potential o establishment of stable
tissue culture lines of spermatogonial stem cells o improvements in
the in vitro development of spermatogonial stem cells into mature
sperm or advanced stages of spermatogenesis o improvements in the
efficiency of transplantation of spermatogonial stem cells into
seminiferous tubules
Since this list is not meant to be all inclusive, prospective
applicants are encouraged to discuss program relevancy issues with
the program staff contact listed under INQUIRIES.  In addition, be
aware that awards made through this RFA would be restricted from
supporting research on attempting to fertilize human eggs or on human
eggs that (1) failed to fertilize, (2) are polyspermic, (3) are
parthenogenetic, either by attempts to specifically activate or that
were discarded after attempted IVF, or (4) are derived from fetal
ovaries with the intent to attempt fertilization or artificial
activation.  Other research on human embryos that is not part of
clinical protocols and/or general procedures in human IVF clinics as
specifically authorized by prior approval of the NICHD is also
restricted from support through an award from 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 is 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
103-43).  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 in the NIH Guide for Grants and Contracts, Vol. 23,
No. 11, March 18, 1994.
Prospective applicants are asked to submit, by May 30, 1997, 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 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.  5/95) is to be
used in applying for these awards.  These forms are available at most
institutional offices of sponsored research; and from the Division of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892, telephone
301-435-0714, e-mail asknih@odrockm1.od.nih.gov.
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 title, MALE GERM CELL GROWTH AND
DIFFERENTIATION, and number, RFA HD-97-004, must be typed on line 2a
of the face page of the application form and the YES box must be
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 to:
Susan Streufert, Ph.D.
Division of Scientific Review
National Institute of Child Health and Human Development
Building 61E, Room 5E03
Bethesda, MD  20892-7510
Bethesda, MD  20852 (for express/courier service)
Telephone:  (301) 496-1485
FAX:  (301) 402-4104
Email:  StreufeS@hd01.nichd.nih.gov
Applications must be received by June 13, 1997.  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
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.  The NICHD will not accept for
review competing new or continuation applications that have been
revised more than one time.  If a revised competing continuation
application is not selected for funding, the applicant institution
may then only submit a new, substantially different application.
Letter of Intent Receipt Date:  May 30, 1997
Application Receipt Date:  June 13, 1997
NACHHD Council Review:     September 1997
Earliest Award Date:       December 1, 1997
Upon receipt, applications will be reviewed for completeness by DRG
and responsiveness to the RFA by NICHD staff. Incomplete applications
will be returned to the applicant without further consideration.  Any
application that does not meet the minimum requirements of this RFA
will be considered unresponsive to the RFA and returned to the
Applications meeting the minimum requirements and 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 usual NIH peer review procedures for
research grants and the review criteria stated below.  As part of the
initial merit review, a process may be used in which applications
will be determined to be competitive or noncompetitive based on their
scientific merit relative to other applications received in response
to this RFA.  Applications determined to be noncompetitive by the
review committee will be withdrawn from further consideration, and
the principal investigator will receive a summary statement
reflecting the reviewers' evaluation.  Applications judged to be
competitive will be further discussed and assigned a priority score.
They will then receive a second level review by the National Advisory
Child Health and Human Development Council (NACHHD).
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;
o  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
o  appropriateness of policies to ensure the protection of human
subjects and the humane care and use of laboratory animals.
The anticipated date of award is December 1, 1997. Applications
approved by the NACHHD Council will be considered for award based
upon scientific and technical merit, program balance, 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 program issues and address the
letter of intent to:
Richard J. Tasca, Ph.D.
Reproductive Sciences Branch
National Institute of Child Health and Human Development
Building 61E, Room 8B01
Bethesda, MD  20892-7510
Telephone:  (301) 496-6515
FAX:  (301) 496-0962
Email:  tascar@hd01.nichd.nih.gov
Direct inquiries regarding fiscal matters to:
Ms. Melinda Nelson
Office of Grants and Contracts
National Institute of Child Health and Human Development
Building 61E, Room 8A17
Bethesda, MD  20892-7510
Telephone:  (301) 496-5481
FAX:  (301) 402-0915
Email:  nelsonm@hd01.nichd.nih.gov
This Program is described in the Catalog of Federal Domestic
Assistance Number 93.864, Population Research.  Awards are made under
the authority 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).  These special Terms of Award are in addition to, and not in
lieu of, otherwise applicable OMB administrative guidelines
administered under PHS grants policies and Federal Regulations 45 CFR
52 and 45 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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