Full Text HD-95-018

MARKERS OF UTERINE RECEPTIVITY FOR BLASTOCYST IMPLANTATION

NIH GUIDE, Volume 24, Number 33, September 22, 1995

RFA:  HD-95-018

P.T. 34

Keywords: 
  Human Reproduction/Fertility 
  Pregnancy 


National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  January 5, 1996
Application Receipt Date:  February 8, 1996

PURPOSE

The National Institute of Child Health and Human Development (NICHD)
invites applications from investigators willing to participate in the
ongoing multisite National Cooperative Program on Markers of Uterine
Receptivity for Blastocyst Implantation with the NICHD through
cooperative agreements.  The primary goal of this Program is to
improve the pregnancy rate in women who have difficulty in conceiving
because of implantation failure.  In order to achieve this goal, it
is expected that investigators will identify markers indicative of
the state of the uterus receptive for blastocyst implantation,
characterize how these markers are involved in the process of
blastocyst implantation, and develop noninvasive methods for
measurement of markers.  It is anticipated that the participating
investigators will cooperate in interdisciplinary and complementary
manners to achieve the goals of identification, characterization, and
measurement of the receptivity markers.  The ultimate beneficiaries
of this Program would be people who have difficulty in attaining a
pregnancy because of implantation failure, and others who may benefit
from assisted reproductive and genetic methods.

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), National Cooperative Program on Markers of
Uterine Receptivity for Blastocyst Implantation, 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).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply.  The need for continuous and active communications and
interactions among sites dictates that only institutions in the
continental United States will be eligible for participation.  This
recompetition is open to both new and competing continuation
applications.

MECHANISM OF SUPPORT

Funding to assist the scientific community in undertaking this
Program of basic and applied research will be through cooperative
agreements (U01) between participating sites and NICHD.  The major
characteristic of a cooperative agreement is substantial scientific
and/or programmatic involvement of the NIH staff Research
Coordinator, above and beyond the levels required by the program
management of grants.  Specifically, an NICHD staff member will
cooperate with the Principal Investigators as a partner in the
research and serve as Research Coordinator.  The Research Coordinator
will assist the recipient(s) in a cooperative way, but without
assuming direction, prime responsibility or a dominant role in the
activity.  In the cooperative agreement, which is an assistance
mechanism and not an acquisition mechanism, the NIH purpose is to
support, stimulate, and expedite the recipient's activities through a
partnership role.  All grantees in this Program will agree to accept
the participatory and cooperative nature of the group process.
Details of the responsibilities, relationships, and governance of the
awards for this Program are discussed later in this document under
Direction and Management: The Steering Committee and in Terms and
Conditions of the Award.

This RFA is a one-time solicitation for the purpose of the present
competition.  At this time, the NICHD has not determined whether or
how this program will be continued beyond the present solicitation.
Any future determination in this regard would be publicly announced.

FUNDS AVAILABLE

An estimated total of $1 million (including direct and indirect
costs) will be available for the entire Program for the first year
with an anticipated four percent increase for future years.

It is anticipated that up to six awards (either new and/or competing
continuation) will be made for a project period of four years with
the start date of December 1, 1996.  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.  Awards and
level of support depend on 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
purpose.

RESEARCH OBJECTIVES

Background

This cooperative program on Markers of Uterine Receptivity for
Blastocyst Implantation was initiated on December 1, 1992 and the
current award period will expire on November 30, 1996.  Four sites
have been participating in the current program, and the program will
be opened for recompetition with anticipation of a greater number of
participating sites and a wider range of research models including
use of human tissues.  The goal of this Cooperative Program is to
identify useful markers that indicate the uterus is, or is going to
be, in the receptive phase for blastocyst implantation and to examine
how these markers, or factors, are involved in the process of
blastocyst implantation.  If it were possible to develop sensitive
assays for such markers in blood, urine, saliva, tears, or
perspiration, major clinical benefits would be feasible.  Basic and
applied research of this nature has significant implications for
important problems in human infertility.  Included among these
problems are:

1.  The uterus accepts a blastocyst for implantation for a limited
period of time (the receptive phase) and then becomes refractory.
Little is known about human markers that would distinguish the
receptive phase from a refractory one.  Such markers are urgently
needed to facilitate treatment of the infertility caused by uterine
refractoriness.

2.  Hormonal treatments that induce ovarian follicle development in
infertile patients perturb the normal sequence of events in the
uterus.  Little is known about what factors in the uterus are
perturbed or how this affects the actual mechanism of blastocyst
implantation.

3.  There are three uterine conditions that indicate uterine
receptivity, i.e., (1) the uterine condition that is receptive for
blastocyst implantation in the fertile cycle and was prepared
hormonally, without the presence of the preimplantation embryo; (2)
the uterine condition that results from hormonal conditioning and the
presence of the preimplantation (and implanting) embryo, and (3) the
uterine condition that predictably procedes, by a certain amount of
time, the forthcoming receptive phase.  Although these conditions are
theoretically distinguishable, it is not known whether or not these
conditions may be distinguished.

4.  The mode of blastocyst implantation varies widely among different
species.  Research on human blastocyst implantation is extremely
limited because of ethical concerns.  So it is imperative to
extrapolate the data obtained from non-human species to understand
human uterine receptivity and blastocyst implantation.  This special
situation necessitates extensive comparative studies between species,
and thus, collaborative studies are essential in this program.

Given the advent of new technologies (such as establishment of the
epoch-making uterine cell culture systems, development and
availability of new reagents such as growth factors and their
antibodies and messages) during the last few years and the persistent
need to improve the pregnancy rate in human in vitro fertilization
clinics, there are still opportunities for research on this central
problem in the clinically-assisted establishment of a pregnancy to
lead to rapid progress.  Such progress will depend upon the use of
newly developed molecular and cellular biological technologies and,
particularly, upon a coordinated, collaborative effort among
researchers of different disciplines who are highly committed to
investigating this problem.  The outcome of this Program's effort to
improve pregnancy rates in humans as well as domestic animals by
prevention of implantation failure will benefit the clinical and
applied fields of the reproductive sciences.  Knowledge gained from
this Program on uterine receptivity for blastocyst implantation will
yield new information about defined markers that can be used to
indicate whether the uterus is receptive or refractory for blastocyst
implantation.  Such knowledge is crucial for selecting the optimal
timing to facilitate the establishment of pregnancy.

Thus, there are both basic and applied scientific needs to clearly
understand the mechanism by which the uterus become receptive to
blastocyst implantation.  This Cooperative Program will lead to
protocols to detect the receptivity of the uterus and will provide a
better understanding of the mechanisms involved in the sequential
interactions between the embryo and the uterus leading to successful
blastocyst implantation.

Since the outset of this Program two and a half years ago, the
Principal Investigators have identified several molecules that appear
on the uterine luminal epithelium prior to and during blastocyst
implantation.  These molecules have temporal and spatial
relationships with blastocyst implantation.  However, markers
identified in the animal model system must be confirmed in the human
to be able to develop noninvasive measurement methods in humans.
Species variability and the cross-reactivity of available reagents
have made it clear that studies on human uterus are necessary to
apply the information obtained in experimental animals to humans.

Recent developments in human uterine investigations indicate that
some molecular substances may serve as good markers for uterine
receptivity.  However, there is very little knowledge about the role
in implantation.  The understanding of human implantation must depend
on studies on experimental animals from which biological samples at
precise stages of pregnancy or a cycle can be obtained for analyses.

When specific markers are identified in uterine endometrial biopsies,
it is necessary to consider how the surgical perturbation encountered
during tissue sampling would affect the physiological sequence of the
endometrial function.  Taking biopsies from the endometrium just
prior to embryo transfer would likely perturb the endometrium where
the transferred embryo is expected to implant.  It is desirable to
avoid the traumatic effects of invasive methods for sampling tissues
to check uterine receptivity.  It is, therefore, important to develop
noninvasive methods to detect useful markers of uterine receptivity.

Objectives and Scope

The major objectives are identification and characterization of
markers useful for indicating that the uterus is, or is going to be,
receptive for blastocyst implantation; to clarify how these markers
are involved in the implantation mechanisms; and to develop
noninvasive methods to detect the markers.  The following are some
examples of research topics, but they are not to be viewed as
exclusive and restrictive:

o  Identification of a marker molecule, for example, a growth factor,
its receptor, or integrin, on the luminal epithelial surface of
endometrium that appears and disappears in parallel with the
initiation and termination of the receptive phase;

o  characterization of adhesion interactions between the apical
surface of uterine luminal epithelial cells and trophoblast to
identify a potential marker molecule;

o  ovarian steroid regulation of a marker molecule;

o  detection of a marker molecule or its metabolite in body fluid to
develop a noninvasive method for the marker;

o  investigation of the role of a marker molecule in the process of
implantation;

o  comparative study of animal and human uterine tissues to determine
applicability of information obtained in the animal to human in terms
of a marker molecule, its isoform, or a related molecule.

SPECIAL REQUIREMENTS

The NICHD invites applications both from current members of the
Cooperative Program (competing continuation applications), and from
prospective members (new applications).  The minimal requirements for
applicants are as follows (see also REVIEW CONSIDERATION below):

o  Competent, experienced principal investigators who are committed
to this problem and who are willing to cooperate with the other
Principal Investigators and the NICHD Research Coordinator;

o  access to properly managed animal colonies with breeding
capabilities and/or access to existing human specimens or tissues
subject to discard;

o  agreement to participate in Steering Committee meetings that will
be held at least twice a year;

o  experience with analyzing, characterizing, localizing and/or
measuring biological molecules and investigating the blastocyst
implantation process.

The following terms and conditions of the cooperative agreement award
and details of the arbitration procedures pertaining to the scope and
nature of the interaction between the NICHD and the participating
awardees will be incorporated into the Notice of Grant Award and
provided to the Principal Investigator and the institutional official
at the time of award.  These procedures will be in addition to the
customary programmatic and financial negotiations that occur in the
administration of grants.

Terms and Conditions of Award

Cooperative agreements are assistance mechanisms subject to the same
administrative requirements as grants.  The special Terms and
Conditions of Award are in addition to, not in lieu of, otherwise
applicable OMB administrative guidelines, HHS, PHS, and NIH grant
regulations, policies and procedures, with particular emphasis on HHS
regulations at 42 CFR Part 74 and 92.  Indirect cost award procedures
will apply to cooperative agreement awards in the same manner as for
grants.  Business management aspects of these awards will be
administered by the NICHD Grants Management Office in accordance with
HHS, PHS, and NIH grant administration requirements.

1.  The Steering Committee

The planning and implementation of the study will be done by a
Steering Committee consisting of the Principal Investigators from
each of the participating sites, one NICHD staff member from the
Reproductive Sciences Branch who will serve as Research Coordinator,
and a nonvoting, independent Chairperson.  To ensure impartiality,
the independent Chairperson will be a scientist of national stature
who is not participating as a Principal Investigator and who is
mutually acceptable to the participants.  The Steering Committee will
meet at least twice a year.

2.  Awardee Responsibilities and Rights

The primary responsibilities of the awardees are:

o  Determine experimental approaches
o  Design protocols
o  Conduct experiments
o  Analyze and interpret the results
o  Present results and plans at Steering Committee meetings
o  Publish results
o  Modify, delete or add protocols within the scientific scope of the
project
o  Accept and participate in the cooperative nature of the group
process.

Awardees will retain custody of, and primary rights to, their data
developed under the award, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies.

3.  The degree of programmatic/scientific assistance by the NICHD
staff Research Coordinator includes:

o  Participation in the development of optimal approaches and
protocol designs (and adjustments of protocols and approaches when
needed).  The Research Coordinator will assist and facilitate the
process, rather than direct it.

o  Assistance and review of all phases of the study to assure
consistency of protocol compliance, to improve and strengthen
cooperation between the sites, and to help redirect efforts,
modifying or terminating a site, if necessary, when performance
requirements are not met.  In the event of disagreement among
participants, the Research Coordinator will assist in forming an
arbitration panel acceptable to participants (see below).

o  Participation in data analyses, interpretation and, when
warranted, publication of study results.

4.  Arbitration

When agreement between an awardee and NIH staff cannot be reached on
scientific/programmatic issues that may arise after the award, an
arbitration panel will be formed.  The panel will consist of one
person selected by the Principal Investigator(s), one person selected
by NICHD staff, and a third person selected by these two members.
The decision of the arbitration panel, by majority vote, will be
binding.  This special arbitration procedure in no way affects the
right of an awardee to appeal an adverse action in accordance with
PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at
45 CFR Part 16.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subgroups 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 new policy results from the NIH
Revitalization Act of 1993 (Section 4928 of Public Law 103-43) and
supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990.  The new policy contains some provisions that are substantially
different from the 1990 policies.

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 reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.  Program staff may also provide additional
information concerning the policy (see INQUIRIES).

LETTER OF INTENT

Prospective applicants are asked to submit, by January 5, 1996, 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 a subsequent application, the information that it contains allows
NICHD staff to estimate the potential review workload and avoid
conflict of interest in the review.

The letter of intent is to be sent to:

Dr. Koji Yoshinaga
Center for Population Research
National Institute of Child Health and Human Development
Building 61E, Room 8B01
6100 Executive Boulevard, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-6515
FAX:  (301) 496-0962
Email:  yoshinak@hd01.nichd.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these cooperative agreements.  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, 6701 Rockledge Drive, Room 3034, MSC
7762, Bethesda, MD 20892-7762, telephone 301/435-0714, email:
girg@drgpo.drg.nih.gov.

Content of Applications

A response to this Request for Applications should include:

o  A description of the capabilities of the site to meet or exceed
the minimal requirements (see SPECIAL REQUIREMENTS above).

o  A proposed four-year research plan that should be the applicant
investigator's perception of the study and of his/her cooperative
role.  This plan should demonstrate the investigator's knowledge,
ingenuity, practicality, and commitment to identify, characterize,
and quantitate a marker(s) of the receptive uterus for blastocyst
implantation.

o  All essential information should be included in the body of the
application rather than in the Appendix.

o  Current members who wish to submit competing continuation
applications should discuss the significant progress they have made
in this Program and may wish to indicate how they met any special
cooperative agreement terms and conditions of their awards including
their interactions with other investigators and the Research
Coordinator if appropriate.  In order to address these aspects more
clearly, current members may, if they so choose, up to five
additional pages in the Progress Report section of their application.

Budget

Since the final protocol(s) for this study will not be exactly known
at the time of submission of the application, the budget request
should be based on the plan proposed by the applicant and should
reflect the scope of the project.  The requested budget should not be
in excess of the amount generally requested for a regular research
grant.  Budgets should not request annual increases for future years
of more than four percent.  Include estimates for staffing needs,
although it is expected that some modification will be needed once
the final research protocol(s) have been developed.  The budget must
also include estimates of travel expenses for two meetings of two
days each of the Steering Committee per year.  The first meeting will
be a planning meeting held in Bethesda, Maryland in December 1996.

Applications must be identified by typing in the RFA number,
HD-95-018, and the RFA Title, MARKERS OF UTERINE RECEPTIVITY FOR
BLASTOCYST IMPLANTATION, on line 2 of the face page of the
application form and the YES box must be checked.  In addition, the
RFA label available in the PHS 398 (rev. 5/95) must be affixed to the
bottom of the face page.  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.

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
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

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
Building 61E, Room 5E03
Bethesda, MD  20892-7510

Applications must be received by February 8, 1996.  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 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.

Timetable

Letter of Intent Receipt Date:  January 5, 1966
Application Receipt Date:       February 8, 1996
NACHHD Council Date:            September 20, 1996
Earliest Award Date:            December 1, 1996

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and for responsiveness by NICHD staff.  Incomplete applications
will be returned to the applicant without further consideration.  Any
application that does not meet the minimum requirements (see SPECIAL
REQUIREMENTS above) of this RFA will be judged to be unresponsive to
this RFA and will be returned to the applicant.

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.  As part of the initial merit
review, all applications will receive a written critique and undergo
a process in which only those applications deemed to have the highest
scientific merit, generally the top half of applications under
review, will be discussed, assigned a priority score, and receive a
second level review by the National Advisory Child Health and Human
Development Council.

Review Criteria

In addition to the usual NIH criteria for scientific merit,
evaluation of the applications will be based upon the following:

1.  Qualifications, experience and commitment of key personnel:

o  Scientific and administrative abilities of the Principal
Investigator and other team members.

o  Knowledge and experience in areas relevant to the conduct of the
experiments proposed.

o  Commitment of time for the proposed study and stated willingness
to work and collaborate with other sites and the NIH in the manner
summarized in this RFA.

2.  Protocols and Procedures

o  Appropriateness of the application to the objectives of the study
as outlined in this RFA.

o  Scientific and technical merit of the proposed research.

o  Where human subjects are involved, 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 human subjects will also be evaluated.

3.  Facilities and Management

o  Availability of resources necessary to perform the proposed
research.

o  Adequacy of administrative and technical capabilities.

o  Adequacy of animal facilities and appropriateness of animal care
management.

o  Institutional assurance to provide support to the study in such
areas as fiscal administration, personnel management, space
allocation, procurement, planning and budgeting.

4.  Budgeting

o  Appropriateness of budget.

5.  Human Subjects, Animal Welfare, Biohazards

o  The initial review group will also examine the provisions for the
protection of human subjects and animals and the safety of the
research environment.

AWARD CRITERIA

The anticipated date of award is December 1, 1996.  Applications
recommended by the NACHHD Council will be considered for award based
upon scientific and technical merit as determined by peer review;
program balance, including in this instance, sufficient compatibility
of features to enhance the likelihood of a successful collaborative
Program; and availability of funds.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is
welcomed.

Direct inquiries regarding scientific issues to:

Koji Yoshinaga, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
Building 61E, Room 8B01
Bethesda, MD  20892-7510
Telephone:  (301) 496-6515
FAX:  (301) 496-0962
E-Mail:  yoshinak@hd01.nichd.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Melinda Nelson
Office of Administrative Management
National Institute of Child Health and Human Development
Building 61E, Room 8A17
Bethesda, MD  20892-7510
Telephone:  (301) 496-5481
FAX:  (301) 496-0915
E-Mail:  nelsonm@hd01.nichd.nih.gov

AUTHORITY AND REGULATIONS

This Program is described in the Catalog of Federal Domestic
Assistance number 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 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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