Release Date:  April 24, 2001

RFA:  RFA-HD-01-012

National Institute of Child Health and Human Development

Letter of Intent Receipt Date:  June 15, 2001
Application Receipt Date:       July 18, 2001


The National Institute of Child Health and Human Development (NICHD) invites 
applications from investigators willing to participate in the multisite 
Cooperative Program on Trophoblast-Maternal Tissue Interactions.  This 
program will utilize the Cooperative Agreement mechanism.  The primary goals 
of this program are:  (1) to assist in establishing healthy pregnancies for 
women who have difficulty in conceiving because of implantation failure, and 
(2) to prevent/alleviate abnormal implantation that would endanger the 
mothers by resulting in preeclampsia or ectopic pregnancy, leading causes of 
maternal mortality in black women.  In order to achieve these goals, it is 
expected that investigators will:  (1) define the receptive state of the 
reproductive tract for blastocyst implantation; (2) characterize how normal 
and abnormal processes of implantation are regulated; (3) develop new 
diagnostic tests for physiological and pathological conditions of the 
endometrium and other parts of the reproductive tract; (4) develop 
noninvasive methods for detecting and preventing abnormal implantation; and 
(5) develop methods to prevent multiple pregnancies in assisted reproductive 
technology while a high pregnancy rate is maintained.  It is anticipated that 
the participating investigators will cooperate in an interdisciplinary manner 
to achieve these goals.  The ultimate beneficiaries of this program will be 
women who have difficulty in attaining healthy pregnancies because of 
implantation failure, and those who suffer from abnormal implantation.


The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of “Healthy People 2010,” a PHS-
led national activity for setting priority areas.  This Request for 
Applications (RFA) is related to one or more of the priority areas.  
Potential applicants may obtain “Healthy People 2010” at 


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 


This RFA will use the National Institutes of Health (NIH) Cooperative 
Research Project Grant (U01) award mechanism, an “assistance” mechanism 
(rather than an “acquisition” mechanism) in which substantial NIH scientific 
and/or programmatic involvement with the awardee is anticipated during 
performance of the activity.  Under the cooperative agreement, the NIH 
purpose is to support and stimulate the recipients’ activity by involvement 
in the activity and otherwise working jointly with the award recipients in a 
partner role, but it is not to assume direction, prime responsibility, or a 
dominant role in the activity.  Details of the responsibilities, 
relationships, and governance of the studies to be funded under cooperative 
agreements are discussed below under Terms and Conditions of Award.


The NICHD intends to commit approximately $1.5 million in total costs [direct 
plus Facilities and Administrative (F&A) costs] in FY2002 to fund up to five 
new grants in response to this RFA.  An applicant may request a project 
period of up to five years and a budget for direct costs of up to $250,000 
for the first year, excluding F & A costs on consortium arrangements.  
Because the nature and scope of the research proposed may vary, it is 
anticipated that the size of each award will also vary.  Although the 
financial plans of the NICHD provide support for this program, awards 
pursuant to this RFA are contingent upon the availability of funds and the 
receipt of a sufficient number of meritorious applications.  At this time, it 
is not known if competing renewal applications will be accepted and/or if 
this RFA will be reissued.



The NICHD supported the initial National Cooperative Program on Markers of 
Uterine Receptivity for Non-human Blastocyst Implantation for four years 
between 1992 and 1996.  This program was recompeted in 1996 and the program 
was renamed the National Cooperative Program on Markers of Uterine 
Receptivity for Blastocyst Implantation.  This latter program is to end in 
November 2001.  This current program has five sites (University of Delaware, 
University of Kansas, University of Illinois, Population Council and 
University of North Carolina).  The purpose of the current program is to 
identify and characterize the molecules that indicate that the uterus is, or 
is going to be, receptive for blastocyst implantation, and to develop 
diagnostic methods to determine the state of the uterine endometrium as to 
its receptivity to blastocyst.

The current group has identified several “marker” molecules that are 
expressed during the receptive period in animal models, and some of them are 
applicable to humans.  In view of successful results and useful knowledge 
gained about endometrial function and molecules expressed under various 
physiological conditions, it was decided to expand the program scope to 
reflect clinical demands to detect, prevent, and/or alleviate abnormal 
implantation that would result in ectopic pregnancy and/or preeclampsia and 
endanger maternal health.  

A list of scientific publications by the current members of the National 
Cooperative Program on Markers of Uterine Receptivity for Blastocyst 
Implantation is available from the program contact listed under INQURIES, 

The goal of this Cooperative Program is to assist in establishing healthy 
pregnancies in women who have difficulty in conceiving because of 
implantation failure, and to prevent/alleviate abnormal implantation that 
would endanger the mothers’ health by resulting in preeclampsia or ectopic 
pregnancy.  In order to investigate abnormal implantation processes such as 
ectopic implantation or preeclampsia, it is necessary to understand the 
normal implantation process and how abnormal implantation differs from 


The major objectives of this RFA are the identification and characterization 
of maternal tissues that allow attachment and implantation of blastocyst, 
particularly molecules that are involved in interactions between trophoblast 
cells and maternal tissues and their components.  It is hoped to identify 
specific molecules that are essential for the initial stages of blastocyst 
implantation, and clarify why implantation fails in the uterus of some 
infertile women.  

The goal of this program is to help establish healthy pregnancy in women.  
However, it is ethically unacceptable to study human implantation.  
Therefore, it is anticipated that investigators will study some aspects of 
human implantation using non-pregnant human reproductive tissues and animal 
model systems applicable to human implantation.  This program will not 
support proposals on human embryos, human in vitro fertilization and embryo 
transfer.  It is expected that investigators will:  (1) identify specific 
molecules that are indicative of physiological/pathophysiological conditions 
of maternal tissue(s), and (2) investigate how these molecules interact with 
molecules on trophoblast in the processes of attachment, invasion, and 
development of tissues that are essential for establishment of pregnancy.

To achieve this goal, applicants are requested to propose the study of a 
selected molecule(s) that is/are considered to play an important role(s) in 
the process of implantation.  Ultimately, investigators participating in the 
program will be expected to study a different combination of molecules, 
systems, approaches, species of animal, and/or tissues from the other 
investigators.  It is anticipated that selected meritorious applications will 
have investigations with unique expertise.  Thus, these projects will 
complement one another.  The selected investigators will form a team and, 
while each investigator will work on his/her project, each investigator will 
also study how his/her molecule or system is related to the molecules/systems 
of other members of the team.    

Research Scope

Most ectopic pregnancies take place in the Fallopian tube.  To prevent 
occurrence of ectopic pregnancy, one has to understand the mechanism of 
embryonic attachment to the tubal epithelium.  Is the mechanism of embryonic 
attachment to the tubal luminal epithelial surface the same as that to the 
uterine luminal epithelium?  Is tubal pregnancy unique to humans?  If so, 
what is the genetic difference between humans and other species of animals?   
Is there a genetic difference between the cell surface of normal tubal 
epithelium and that of a woman who suffers from ectopic pregnancy?  Can we 
attribute the reported health disparity in the occurrence of  tubal pregnancy 
to expression of specific gene(s) on the tubal epithelium?  Much information 
is needed in this research area.

Interactions between trophoblast and maternal tissues in early stages of 
pregnancy involve interactions between trophoblast and maternal luminal 
epithelium, basement membrane, stromal cells, extracellular matrix 
components, and maternal blood vessels.  Although there are various aspects 
to the interactions between trophoblast and maternal tissues, this program 
places special focus on gene expression and its regulation in the process of  
blastocyst implantation.

Examples of research topics that fall within the scope of the program 
include, but are not limited to, the following:

o  identification of essential molecules that are expressed at the site of 
trophoblast-maternal tissue interactions;

o  investigation of the physiological or patho-physiological role of the 
identified molecule(s) in the normal, abnormal, or failing implantation 
o  application of information obtained in animal models to human reproductive 
tissues to verify the significance of animal work;

o  detection and prevention of ectopic pregnancy based on regulation of 
identified molecules in the process of implantation;

o  development of animal models to increase the successful implantation rate 
of a transferred single embryo to provide useful information for prevention 
of multiple pregnancies in humans.  

Guidance and Management Structure

The overall guidance and management of the program will be provided by a 
Steering Committee consisting of the Principal Investigators of each of the 
participating sites, one NICHD staff member from the Reproductive Sciences 
Branch who will serve as Research Coordinator, and a nonvoting, independent 


Minimum Application Requirements

The NICHD invites applications both from current members of the Uterine 
Receptivity Cooperative Program and from new applicants.  Because of the 
change of the research scope, all applications will be considered new 
applications.  The minimum requirements for applicants are as follows (see 
o  a competent, experienced Principal Investigator who is committed to 
investigation of these problems and who is 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.


Principal Investigators are expected to attend two Steering Committee 
meetings of two days each per year.  The first meeting will be a planning 
meeting held in Bethesda, Maryland in February 2002.

Terms and Conditions of Award

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.

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.  Facilities and administrative cost (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 Branch in accordance with HHS, PHS, and NIH grant 
administration requirements.

1. The Primary Rights and Responsibilities of the Awardees

The primary rights and responsibilities of the awardees are to:

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 

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. 

2. NICHD Responsibilities

NICHD Research Coordinator:

The NICHD Research Coordinator will be a staff member of the Reproductive 
Sciences Branch.  The Research Coordinator is a partner within the program, 
representing the government’s interest in the substantive work of the 
participating investigators.  The primary role of the Research Coordinator is 
to facilitate the work of the investigators through the following activities:

o  participation in the development of optional 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, when 
performance requirements are not met.

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

The above responsibilities are in addition to, not in lieu of, the levels of 
involvement normally required for program stewardship of grants.

NICHD Project Officer:

NICHD will appoint a Project Officer, apart from the Research Coordinator, 
who will:

o  have the option to withhold support to a participating institution if 
technical performance requirements are not met.

o  carry out continuous review of all activities to ensure objectives are 
being met.

3. Collaborative Responsibilities

The planning and implementation of the studies will be done by a Steering 
Committee consisting of the Principal Investigators from each of the 
participating sites, the NICHD 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.

4. Arbitration Procedures

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 regulation at 42 CFR Part 50, Subpart 
D, and HHS regulations at 45 CFR Part 16.


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 indicating 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 
UPDATED “NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research,” published in the NIH Guide for Grants and Contracts on 
August 2, 2000 
a complete copy of the updated Guidelines is available at  The 
revisions relate to NIH-defined Phase III clinical trials and require:  a) 
all applications or proposals and/or protocols to provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) all investigators to report accrual, and to conduct and report 
analyses, as appropriate, by sex/gender, and/or racial/ethnic group 


It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them.  
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
“NIH Policy and Guidelines on the Inclusion of Children as Participants in 
Research Involving Human Subjects,” published in the NIH Guide for Grants and 
Contracts, March 6, 1998, and available on the Internet at:  

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


All applications and proposals for NIH funding must be self-contained within 
specified page limitations.  Unless otherwise specified in an NIH 
solicitation, Internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to review the Internet sites.  Reviewers are cautioned that their anonymity 
may be compromised when they directly access an Internet site.


Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, telephone 
number, and e-mail address of the Principal Investigator, the identities of 
other key personnel and participating institutions, and the number and title 
of this RFA.  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 plan the review.

The letter of intent is to be sent to Dr. Koji Yoshinaga, at the address 
listed under INQUIRIES, below, by June 15, 2001.


The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants.  These forms are available at most institutional 
offices of sponsored research, on the Internet at, and 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, E-mail:

Application Instructions

An application in response to this RFA 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 five-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 
essential molecules expressed at the site of the trophoblast-maternal tissue 

o  all essential information should be included in the body of the 
application rather than in the appendix.


Since the final protocol(s) for this study will not be 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. 
Budgets should not request annual increases for future years of more than 
three 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 requests for travel 
expenses for two meetings per year of the Steering Committee, lasting two 
days each.  The first meeting will be a planning meeting held in Bethesda, 
Maryland in February 2002.

Submission Instructions

The RFA label available in the PHS 398 (rev. 4/98) application form must be 
stapled to the bottom of the face page of the application and must display 
the RFA number, HD-01-012.   A sample RFA label is available at  Please note this 
is the pdf format.  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 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 should be 
sent to:

L. R. Stanford, Ph.D.
Director, Division of  Scientific Review
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 5E03F, MSC 7510
Bethesda, MD 20892-7510
Rockville, MD 20852  (for express/courier service)

Applications must be received by July 18, 2001.  If an application is 
received after that date, it will be returned to the applicant without 

The Center for Scientific Review (CSR) will not accept an application in 
response to this RFA that is essentially the same as one currently pending 
initial review, unless the applicant withdraws the pending application.  CSR 
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 for completeness by the CSR and 
for responsiveness to this RFA by NICHD staff.  Incomplete and/or 
nonresponsive applications will be returned to the applicant without further 
consideration.  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, all applications will receive a 
written critique and may undergo a process in which only those applications 
deemed to have the highest scientific merit 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

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health. In 
the written comments, reviewers will be asked to discuss the following 
aspects of the application in order to judge the likelihood that the proposed 
research will have a substantial impact on the pursuit of these goals. Each 
of these criteria will be addressed and considered in assigning the overall 
score, weighting them as appropriate for each application. Note that the 
application does not need to be strong in all categories to be judged likely 
to have major scientific impact and thus deserve a high priority score. For 
example, an investigator may propose to carry out important work that by its 
nature is not innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem?  If the aims 
of the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or 
methods?  Are the aims original and innovative?  Does the project challenge 
existing paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited 
to carry out this work? Is the work proposed appropriate to the experience 
level of the Principal Investigator and other researchers (if any)?

(5) Environment:  Does the scientific environment in which the work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

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

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project 
proposed in the application.


Letter of Intent Receipt Date:    June 15, 2001
Application Receipt Date:         July 18, 2001
Peer Review Date:                 October/November 2001
Council Review:                   January 2002
Earliest Anticipated Award Date:  February 1, 2002


Criteria that will be used to make award decisions include:

o scientific merit (as determined by peer review);
o availability of funds;
o programmatic priorities;
o sufficient compatibility of features to enhance the likelihood of a 
successful collaborative program.


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

Direct inquiries regarding programmatic issues to:

Koji Yoshinaga, Ph.D.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard,  Room 8B01, MSC 7510
Bethesda, MD 20892-7510
Telephone:  301-496-6515
FAX:  301-480-2389

Direct inquiries regarding fiscal matters to:

Ms. Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17, MSC 7510
Bethesda, MD 20892-7510
Telephone:  301-496-5482
FAX:  301-402-0915


This program is described in the Catalog of Federal Domestic Assistance No. 
93.864, Population Research.  Awards are made under authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and administered under NIH grants policies and Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  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 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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