Interdisciplinary Collaborative Team for Blastocyst Implantation Research: inception and...

Interdisciplinary Collaborative Team forBlastocyst Implantation Research: inception and

perspectives

To the editor:

Research coordinators description of the Team

(Koji Yoshinaga and Mercy PrabhuDas, NIH)

This study describes the currently active research

team created by participation of investigators who

are eager to work together with other investigators

of different disciplines on implantation research. The

name of this group is ‘Interdisciplinary Collaborative

Team for Blastocyst Implantation Research’. From

now on we will call the group the Team. It started

with the publication of an NIH Program Announce-

ment.

Program Announcement

Background

Study of human implantation has at least two major

difficulties: (i) ethically one usually cannot obtain

the samples of implanted human embryo, and (ii)

there are no ideal experimental model animals that

represent human implantation. Despite these diffi-

culties, the mission of research on reproduction

necessitates understanding and clarification of the

process of implantation of a human embryo in order

to diagnose and treat infertility caused by implanta-

tion failure. It is estimated that approximately 50%

of fertilized embryos fail to result in healthy babies.

Because we do not have a single animal model that

represents the human, it is imperative to obtain

pieces of information from other species of animals,

non-pregnant human uterus and cell lines. The

obtained pieces of information need to be integrated

by experts, and the human implantation process

must be extrapolated from the obtained information.

Issuance of PA-07-445 [Interdisciplinary Research on

Implantation (R01)]

To form a group of experts on implantation research,

PA-07-4451 was published in September 2007. In

response to this program announcement (PA), a

total of 26 R01 applications were submitted during

the 3-year period, and each application was

reviewed by an appropriate Center for Scientific

Review (CSR) study section. A total of three applica-

tions were funded during this time. Although the PA

was published, some researchers were not aware of

the PA, and they learned the existence of the PA

after a grant was funded. In such a case, the Team

members decided to accept such a researcher who

had been newly funded with an R01 grant when all

of the Team members unanimously agreed to accept

as a member.

Administrative collaboration between Institutes

The Team serves as a forum for the scientists to col-

laborate among themselves in their research areas of

interest. Soon after the PA-07-445 was published,

Koji Yoshinaga discussed the announcement with

colleagues from the Basic Immunology Branch of

NIAID to foster collaboration between the institutes.

This began a collaborative effort between the two

institutes (NICHD and NIAID) since the immunology

of reproduction was a common interest. Since NIAID

supports basic research on interactions between the

immune system and components of the reproductive

system, researchers with research project grants are

welcome to become Team members. Thus, Mercy

PrabhuDas was invited to become co-research coor-

dinator of the Team. Mercy joined the Team in

October 2010. Mercy provides not only administra-

tive information from NIAID but also actively joins

the discussions from the immunological point of

view. Thus, the Team members gain NIH administra-

tive and scientific information from both NICHD and

NIAID program staff.

TEAM Formation and Meetings

The response of the scientific community to PA-07-

445 was different from those of Request for Applica-

tions (RFA) published on uterine receptivity for

implantation, or on trophoblast–maternal tissue

interactions. The enquiries that were received

regarding the PA were from new and young investi-

gators. Many of them were interested in the concept

of an interdisciplinary approach. On the other hand,

those who responded to the RFAs were, more often,

American Journal of Reproductive Immunology 71 (2014) 1–11

ª 2013 John Wiley & Sons Ltd 1

LETTER TO THE EDITOR

investigators involved in the limited research area of

implantation.

It has been a little over 5 years since NIH pub-

lished a Program Announcement (PA-07-445) on

forming a collaborative team to study implantation

in 2007. This program announcement (PA) is unique

in that there are no set-aside funds and participants

must obtain an NIH R01 grant on his/her research

project in order to participate in the Team. The Team

members initially met semi-annually to report their

progress, discuss experimental data, and plan experi-

ments for the next period of 6 months or so. Partici-

pants are responsible for their travel and

accommodation costs from their grants. The Team

members meet at NIH and the Research Coordinator

arranges the meeting. Research Coordinators are

responsible for maintaining the group activity and

for advertising the group to the research community.

One of such activities is to publicize the Team at sci-

entific meetings2 and in newsletter publications.

The first grant on this program was funded in Sep-

tember of 2008 to a multiple Principal Investigator

(P.I.) – directed R01 by Drs. Christopher Davies and

Kenneth White of Utah State University on ‘Tropho-

blast MHC-I: Trigger for immune-mediated rejection

of cloned bovine fetuses’. The second R01 grant was

funded in April of 2009 to Dr. Kathleen Caron of

University of North Carolina on ‘Adrenomedullin

signaling at the maternal–fetal interface’. As soon as

the second grant was funded, the inaugural meeting

of the Team was held in May 2009. This first meet-

ing with four people remains with me as the most

emotional meeting in my life, and I cannot forget

the thrilling sensation of having initiated the new

and exciting research activity at NIH.

The third grant was funded in August 2009 to Dr.

Thaddeus Golos of University of Wisconsin on ‘Uter-

ine NK cells in primate pregnancy’. This third grant

was funded with funds from President Obama’s

American Recovery and Reinvestment Act. The sec-

ond Team meeting was held in October 2009 with

three projects. At this meeting, the members agreed

upon a procedure, in addition to the PA-responsive

grantees, to recruit new members from those

recently funded grantees and those who expressed a

desire to join the Team. Unanimous consent of the

current Team members is required for prospective

members.

Dr. Asgerally Fazleabas of University of Illinois at

Chicago (at that time) requested to join the Team in

April 2009. The Team unanimously agreed to

welcome Asgi, and his project was the fourth of the

Team in November 2009. Dr. Fazleabas’ project was

on ‘Modulation of the receptive endometrium by

chorionic gonadotropin (CG)’. Since Asgi’s project

used baboon as a model system, the Team became

suddenly enriched with primate research by adding

two projects working on non-human primates. Dr.

B.C. Paria of Vanderbilt University wrote an R01

application on natriuretic peptides and implantation

and requested to join the Team after the grant was

funded. His request was reviewed by the members

and unanimously accepted Dr. B.C. Paria with the

fifth project of the Team in January of 2010.

The third Team meeting was held in April 2010.

There were a total of seven members at this time.

Dr. Gil Mor of Yale University organized a Pro-

gram Project grant (P01) on toll-like receptors

throughout pregnancy, and the proposal was funded

in October of 2009. Dr. Mor’s subproject was on

‘Role of Toll-like receptors in trophoblast immune

regulation’. Dr. Mor was interested in joining the

Team with an R01. Since projects within a P01

were considered equivalent to R01s, the Team con-

sidered Dr. Mor’s P01 project appropriate for joining

the Team. Dr. Mor was enthusiastically invited to

be a Team member as the investigator on the sixth

project of the Team. Dr. Soumen Paul’s interest is

in trophoblast lineages. He received an R01 grant

on GATA factor function in trophoblasts. Since

implantation is a series of interactions between the

trophoblast and maternal tissues, and interactions

vary depending on the location of the embryo–maternal interface, he was approached to determine

his interest in joining the Team. Dr. Paul positively

responded, and the members unanimously agreed

to accept Dr. Paul as the seventh project of the

Team. Dr. Mercy PrabhuDas of NIAID was invited

to join the Team as co-research coordinator at this

time. Dr. PrabhuDas’ role is very important

because of her immunology background, and she

provides relevant information from NIAID for the

investigators.

The fourth Team meeting was held with seven

projects and eight investigators, and ten Team mem-

bers in October of 2010. At this meeting, the mem-

bers discussed the future direction of this Team. It

was a general opinion that because researchers

needed a longer interval than 6 months between

meetings for production of adequate data, and for

fiscal reasons, the Team members decided to meet

every 8–9 months.


2 ª 2013 John Wiley & Sons Ltd


The fifth Team meeting was held in June 2011

with seven projects and eight investigators, and ten

Team members.

An R01 submitted in response to the PA by Dr.

Xiaoqin Ye of University of Georgia was co-funded by

NICHD and the Office of Research on Woman’s

Health in November 2011. Dr. Ye’s project was on the

interaction of molecular signaling involving lysophos-

phatidic acid receptor and progesterone receptor in

the uterine receptivity for implantation. This is the

eighth and the last PA-responsive project that joined

the Team. From this time on all new projects had to

be reviewed by the Team members and the P.I. of the

project may become a Team member with unanimous

agreement of the members. Dr. S.K. Dey of Cincinnati

Children’s Hospital Medical Center submitted a grant

on muscle segment homeobox (Msx) family members

in the uterine receptivity for implantation. This grant

was funded in October 2011, and he expressed an

interest in joining the Team. The Team members

enthusiastically agreed to accept Dr. Dey as a Team

member as the ninth project of the Team.

The sixth Team meeting was held in February

2012 with nine projects, ten investigators, and 12

Team members. At this meeting, the Team agreed to

invite Dr. Jane Salmon of Cornell University to be a

guest speaker at the seventh meeting. Dr. Salmon,

Dr. Kathleen Caron’s collaborator, was invited to

emphasize and discuss translational research in early

pregnancy from her research experience.

Dr. Thomas Spencer of Washington State Univer-

sity submitted his R01 application on uterine recep-

tivity in cows in response to the USDA-NIH

collaborative support program announcement (PAR-

10-276) titled ‘Dual purpose with dual benefit:

Research in biomedicine and agriculture using agri-

culturally important domestic species (R01)’. Using

the systems biological approach, Dr. Spencer plans to

advance our knowledge on uterine receptivity for

implantation in cows. This grant was funded in

August 2012 and was transferred to our program.

Dr. Spencer’s request to join the Team member with

this project was unanimously accepted by the Team

members. Dr. Spencer’s project is the tenth project

of this Collaborative Team. In January 2013, Dr. R.

Michael Roberts of University of Missouri asked to

join the Team and his request was whole-heartedly

accepted by the Team. The project of Dr. Roberts

focuses on pluripotent human stem cells as models

for normal and diseased trophoblasts, and is the

11th project of the Team.

You can see in Table I the Team has been growing

steadily over time. One of the unique features of this

Team is that members join the Team at different times

as they obtain one’s own R01 grant. Since members

stay in the Team throughout the grant period, the

Team remains open and evolving. Although this pro-

gram was initiated with the publication of the pro-

gram announcement (PA-07-445), the PA has now

expired. The current method of joining the Team is to

obtain an R01 grant and to obtain unanimous consent

of the members through the research coordinator.

Comparison between Collaborative Team (R01)

and Cooperative Agreement (U01)

Here, we compare two types of collaborative mecha-

nisms at NIH: [A] this Collaborative Team using the

R01 grant mechanism and [B] the NIH traditional

Cooperative Agreement using U01/U19 grants. (i) [A]

does not have set-aside funds to support responsive

applications; thus, each applicant must compete for

the Institute research project grant budget, while [B]

has set aside funds; (ii) [A] Announcement of this

program is made in a PA which is effective for 3 years;

thus, applicants can submit R01 applications at any-

time during the 3 years, while the Announcement of

the Cooperative Agreement program [B] is made via a

Funding Opportunity Announcement as a RFA, and

the submission of applications in response to the RFA

is usually only on one date; (iii) In [A], the Review

panel (study section) may be chosen by the applicant,

while reviews are usually done by an Institute-desig-

nated special review panel for [B]; (iv) The duration

of program may be as long as the participating investi-

gators’ project periods in [A]. Since members join the

Team in a staggering fashion, old members may

renew their R01s when their project period ends, and

successful competing renewal grants are eligible to

continue membership. In [B], the project usually ends

after a 5-year period. Reissuance of an RFA on the

same or similar topic may start another 5-year project

Table I Number of Projects in the TEAM is Rapidly Growing

2009

(spring)

2009

(fall) 2010 2011 2012 2013

No. Projects 2 3 5 7 10 11

No.

Investigators

3 4 6 8 11 12




period, but there is no continuity between the first

and the second groups. (v) In [A], new members may

join the Team whenever an R01 is funded with the

consent of the current members; in [B], new members

are unable to join the group. These differences are

summarized in Table II.

The Cooperative Agreement is a very strong sup-

porting mechanism, and collaborative work done

using this mechanism is greater than the sum of the

same number of individual R01s.

Scientific Goals of the Team

This is a collaborative group of scientists with a

research focus on the attachment of an embryo to the

uterine wall to initiate pregnancy. The ultimate goal is

to understand human implantation to diagnose and

prevent infertility caused by implantation failure.

Extreme difficulty in conducting research on human

pregnancy made it necessary to work on many model

systems and cell lines to extrapolate the obtained data

to construct the cellular and molecular mechanisms

involved in human implantation. Strong interest and

enthusiasm of the Team members have made the

development of the Team and its activities possible.

The first collaborative paper3 was published in 2012.

Enquiries on joining the Team continue from the

research community. We hope new members will

continue to join the Team and the Team projects as a

whole will gradually change as early projects termi-

nate in 5 years and new projects continue to come in.

This is the evolutionary nature of this collaborative

research group. Unlike a one-time Cooperative Agree-

ment group of U01 research projects, this Collabora-

tive Team of R01s has a long life, as long as the

researchers want to maintain the collaboration using

this system. At each Team meeting, we are excited

with the enthusiasm and interest of the Team mem-

bers and this ardency of the members always reminds

one of the elevated sentiments at the very first inau-

gural Team meeting held with only four members.

Team members’ comments

Christopher Davies and Kenneth White (Utah State

University, Logan, UT) members since 2009

As new investigators within the NIH system, forma-

tion of the ‘Interdisciplinary Collaborative Team for

Blastocyst Implantation Research’ has fostered our

integration into the NICHD research community.

We were excited when Dr. Yoshinaga sent us a copy

of PA-07-445 shortly after it was published in Sep-

tember 2007 as it was clear that our R01 grant pro-

posal entitled ‘Trophoblast MHC-I: Trigger for

Immune-Mediated Rejection of Cloned Bovine

Fetuses’ was an excellent fit for this program. Con-

sequently, when we resubmitted our grant proposal

in November of 2007 we submitted it in response to

PA-07-445. We are honored that our grant was

funded as the initial grant submitted under this PA.

It has been wonderful to watch the collaborative

team develop and to take part in the intellectually

stimulating group meetings. The meetings have

helped us strengthen old friendships, develop new

friendships, and build new collaborations. Meeting

with the diverse group of scientists who comprise

the collaborative team on a regular basis and dis-

cussing everyone’s projects, which involve a variety

of animal models, as they develop and evolve has

allowed us to gain unique insights. The team meet-

ings have inspired us to reflect on how a variety of

cellular and molecular interactions contribute to the

processes of embryo attachment, maternal adapta-

tion and acceptance of the conceptus, and fetal

development. The strong leadership of Drs. Yoshina-

ga and PrabhuDas and the commitment of the team

members have helped the team develop into a

strong scientific community that encourages its

members to develop new ideas and grow scientifi-

cally.

Table II Comparison of Two Supporting Collaborating Group

Support Mechanisms [Collaborative Team (A) and Cooperative

Agreement (B)]

A B

Collaborative

Team (R01)

Cooperative

Agreement (U01)

Announcement

method

PA RFA

Set-aside funds No Yes

Application

submission

Any time during

3 years

One designated

time

Application review CSR study section Special emphasis

panel

Duration of

program

As long as

members retain

R01

5 years

Joining the group At any time Only once at the

beginning




Kathleen Caron (University of North Carolina,

Chapel Hill, NC), member since 2009

The name says it all! As one of the founding mem-

bers of the ‘Collaborative Team on Interdisciplinary

Research on Blastocyst Implantation’, there are

many reasons for which I find participation in this

activity highly beneficial to our research productiv-

ity.

The word ‘Collaborative’ really embodies the

atmosphere of our group gatherings. Each participat-

ing member shares their latest data, hot off the

presses, for candid and helpful input from other

members of the Team. We are there to provide

advice and find connections between our research

projects, with the ultimate goal of collectively

advancing our scientific programs. In many

instances, I have taken the advice of my colleagues

to venture into new and unexpected directions, and

likewise, my laboratory has been delighted to con-

tribute to several ongoing studies of other Team

members.

The word ‘Team’ has changed since our first

meeting 4 years ago. From 3 to 13 – our group has

steadily expanded and now includes experts from

across the country. Teams work together and make

decisions together – and this is true of our group.

We begin each session with an Administrative

Review of our activities. In these discussions, we

share thoughts about either expanding or focusing

the scope of our group and we set the stage for

future meetings. And because we are a Team, we

must all agree!‘Interdisciplinary Research’ is a buzz word that

can mean many things. For our group, it appropri-

ately conveys the amazingly wide breadth of model

systems that we use embryonic stem cells, primates,

cows, hamsters, mice, and humans. The techniques

used by our group are equally impressive and

encompass all of the ‘-omics’ technologies alongside

incredibly sophisticated surgical models, cloning

approaches, and genetic engineering. Since it is diffi-

cult to study human implantation, I believe that we

are best served by incorporating a wide variety of

model systems in order to extrapolate our findings

to human health and disease. Equally important has

been the strong assimilation of immunological

aspects of implantation and participation of NIAID in

our Team meetings, which strengthen our ability to

recognize interdisciplinary links between the

immune system and reproductive physiology.

However, an important word that is missing from

our name is ‘Fun’! Attending our Team meetings is

one of the highlights of my travel schedule. We have

loads of fun. Who would have thought that

preparing for a laboratory meeting presentation

every 6 months would be so invigorating? Having

the opportunity to get to know the members of the

Team and NIH Program Officials as close friends and

colleagues has been a true honor and delight. In a

rapidly changing scientific world, building Teams

and fostering interdisciplinary collaboration should

be our top priority. Therefore, I strongly encourage

NICHD and other NIH Institutes to continue to sup-

port this innovative model of Team Building.

Thaddeus Golos (University of Wisconsin,

Madison, WI), member since 2009

What made you join the Team? I have been success-

fully funded by NIH grants since 1989, and have

particularly been fortunate to know Dr. Koji Yoshi-

naga for many of these years. I read Koji’s papers on

implantation as a graduate student and as a begin-

ning faculty member moving into the implantation

field and when the original PA-07-445, Interdisciplin-

ary Research on Implantation was announced, I recog-

nized this as a unique opportunity. While U54 or

P01 mechanisms exist to support collaborative

research, these are expensive, highly competitive, or

constrained by the need for existing collaborations.

This PA provided an opportunity for in-depth dialog

and examination of data, primarily unpublished, to

get feedback from outstanding investigators in the

area of implantation. Few institutions have the mass

of investigators in this area to provide such high-

level interactions and Koji’s initiative was very entic-

ing.

What benefit did you get by joining the Team? I was

the third member of the team. When I joined,

although the group was small, there was immediate

benefit and intellectual stimulation provided. For

example, Drs. Davies and White discussed at length

their deep sequencing of the bovine placental MHC

class I molecules, an area I had been working in for

many years with the rhesus monkey. However, my

laboratory had not taken the next step for upgrading

our technical approaches and this was a great oppor-

tunity for me to discuss at length advantages and

disadvantages of specific approaches, discuss unpub-

lished data from our two laboratories, and initiate a

new course of action in our work. We did submit a




grant proposing to define placental MHC polymor-

phism with advanced sequencing methodologies and

while not yet funded, this has become the basis of a

graduate student’s thesis.

For another example, when Soumen Paul joined

the group, we discussed his work with trophoblast

differentiation of embryonic stem cells, and our own

studies with rhesus blastocysts. We initiated a collab-

oration and provided in vitro fertilization (IVF)-

derived rhesus blastocysts for his work on trophecto-

derm lineage formation, which was published in

PNAS in 2012. Finally, my work has included repro-

ductive immunology since 1995, and several of my

grants have been funded by NIAID. Koji wisely

invited Dr. Mercy PrabhuDas from the NIAID to par-

ticipate in the meetings. Her presence has provided

the Team members with information and updates on

how to enhance the dual feasibility of our proposals,

particularly in the context of reproductive tract

infections and adverse pregnancy outcomes, which

is an area my laboratory has been moving toward

with the primate model in order to enhance transla-

tional opportunities for improving maternal and fetal

health. I think cross-institute dialog has been a great

opportunity and I applaud both Program Officers

(POs) for their reaching across the institute (IC) gap

in support of the science.

These are three tangible examples of the scientific

benefits of joining the Interdisciplinary Team. Over-

all, the main benefit is that there can be several days

of focused discussion that allows a depth of discus-

sion beyond what is usually found at large confer-

ences.

What is your future perspective of this mechanism? I

believe that the Collaborative Team approach can

work very well, given thoughtful leadership and

dedication to the process by the members of the

Team. There are a few areas that could be detrimen-

tal to the Team approach. Although everyone’s time

is short, given the pace of research, all members

should agree to meetings at which everyone arrives

on time, and stays through the duration, unless

extenuating circumstances prevent it. I also think

there should probably be discussion as to the optimal

size for a Collaborative Team. As the size of a Team

grows, there is danger that the quality of the discus-

sion may suffer. Perhaps insuring that only appli-

cants willing to adhere to the Team guidelines are

accepted for participation will sustain the high qual-

ity of dialog that I found during the first years when

the team was relatively small. Nonetheless, I hope

that the Team model is tried by other POs in NICHD

especially where opportunities exist for cross-insti-

tute support and interactions.

Asgerally Fazleabas (Michigan State University,

Grand Rapids, MI), member since 2009

I believe that collaborative research is the corner-

stone of scientific discovery and accelerated progress.

I was fortunate to be funded for 10 years (1992–2001) through the U01 mechanism that was focused

on ‘Uterine Receptivity for Implantation’ of which

Dr. Koji Yoshinaga was the Program Officer. A cen-

tral question that needed to be addressed was to

determine if in the primate, as has been identified in

other species, that the embryonic signal could modu-

late the uterine environment specifically. The clinical

and translational relevance of this question was

directly related to the poor implantation rates that

plagued assisted reproductive therapies then and

even continues to some extent today. Therefore, the

identification of markers of endometrial receptivity

was important then as it is still today. During the

initial funding period of this collaborative effort my

laboratory established a non-human primate model

in which we could simulate the intra-uterine milieu

of early pregnancy. These studies provided the first

in vivo evidence that infusion of CG into the uterine

cavity during the window of implantation markedly

alters the morphology and gene expression of the

uterine endometrium. The development of this

model resulted in many collaborations with other

members of the group in which we undertook

extensive collaborative studies on the regulation of

‘pinopods’ within the window of uterine receptivity,

the changes in MUC1, COX2, and avb3 integrin

expression to just name a few. We were also able to

demonstrate the synergism that was essential

between signals from the embryo and progesterone

for the establishment of uterine receptivity in the

primate. As a group, we were able to undertake a

series of comparative studies between rodents, non-

human primates and women and were able to

define both the common and unique pathways that

govern the conditions that are optimal for embryo

implantation. A further strength of this collaborative

effort was that we as a group could test multiple

hypotheses using several different model systems.

The close interaction and twice yearly meetings as

well as exchanges between each other’s laboratories

truly facilitated this effort which could never have




been accomplished without this type of focused

effort, common scientific goals, and mutual trust

that was clearly established. The program was highly

successful and as a group we published 96 manu-

scripts collaboratively during this 10-year period.

In 2001, a new RFA focused more on ‘Tropho-

blast–maternal tissue interactions’ was published. A

new group was brought together and in the light of

my R01 funding related to decidualization I was

asked to join the group although my application was

not part of the U01 mechanism. Buoyed by the spirit

of collaboration of the previous 10 years I joined the

new group and this provided me with insights into

placental biology that led to important studies

focused on other embryonic and trophoblast signals

that could specifically modulate decidual function.

Again as a group, we were able to undertake exten-

sive global gene expression analyses and develop

gene signatures associated with trophoblast–maternal

interactions.

I firmly believe that these focused collaborative

studies have laid the groundwork for insights into

some of the pressing clinical problems that are being

currently addressed, that is, the development of pro-

gesterone resistance as a consequence of endometri-

osis, the use of intra-uterine hCG to improve

pregnancy rates with assisted reproductive therapies

and the concept that the decidua acts as an embry-

onic biosensor and aberration of this response is

associated with recurrent pregnancy loss and

preterm labor.

As successful as the outcome of 15 years (1991–2005) of set aside funds had been, the focused nat-

ure of the research area as well as the fiscal reality

made it unrealistic to continue to have set aside

funds for this endeavor. In 2007, a PA (07-445) was

issued that focused on ‘Interdisciplinary Research on

Implantation’. Although my current R01 (initially

funded in 2003) did not specifically respond to the

PA, the excitement of once again being part of a col-

laborative and interdisciplinary group and being able

to address scientific questions that could only be

undertaken in a collaborative manner prompted me

to request to join this group in 2009. From its initial

formation, the group has grown significantly and it

is now much more diverse. This diversity also brings

richness of scientific thought and discourse. The

focus on both the immune system as well as endo-

metrial biology brings together expertise to under-

stand the unique properties of the fetal allograft, its

stem-like properties and the mechanisms by which

the endometrium accommodates the developing

fetus. The ‘immune-endocrine’ interface is of signifi-

cance to both fundamental biology as well as repro-

ductive pathologies that are associated with

disturbances of the immune system. No single labo-

ratory can address this complex paradigm and col-

laboration between investigators with different

expertise will be critical for understanding the com-

plexity of the reproductive process particularly at the

time of implantation.

Bibhash Paria (Vanderbilt University, Nashville,

TN), member since 2009

The focus of my research work is to understand the

basic mechanisms of implantation, decidualization,

and pregnancy protection. In particular, my labora-

tory at VUMC is trying to define the role of natri-

uretic peptides in implantation and decidualization

using the hamster as an animal model. When I

heard about the Interdisciplinary Collaborative Team

Program in ‘revealing the aspects of implantation’ I

got excited to join since the program is developed to

support a well-defined central theme with multiple

distinct but synergistic projects build around it.

There is no doubt that it is necessary to bring

together investigators from varied disciplines because

their existing activities and capabilities cohesively

will help to enhance the investigators’ existing capa-

bilities or to develop new approaches to the overall

research goal that would not be possible otherwise.

Dr. Koji Yoshinaga who has initiated this program

has assembled a strong multidisciplinary team con-

sisting of developmental biologists, stem cell biolo-

gists, immunologists, and reproductive biologists

who share a common research interest in implanta-

tion physiology. Looking at the list of team members

of this program, I realized that all of these investiga-

tors are experts in their own research field and have

deep knowledge to share their thoughts and ques-

tions. Without a second thought, I joined the team.

The team members helped me to develop a research

area to study the barrier aspects of the uterus to

protect implantation as well as pregnancy against

infection, and are checking the progress along the

way. As a whole, this program is growing strong

and all like-minded forward-thinking members are

dedicated to making fundamental contributions to

the implantation field with their innovative

thoughts and collective knowledge, skills, and team-

work.




Gil Mor (Yale University, New Haven, CT),

member since 2010

The Reproductive Immunology Unit at Yale Univer-

sity was established in 2001 with the objective of

uniting the advances made in the fields of immunol-

ogy and reproduction. Both of these areas have

advanced significantly over the last decade eliciting a

major challenge to advance the evolutionary growth

of reproductive immunology and provide new

aspects that will benefit our patients. A major key-

stone of the Unit was the funding of our P01, whose

objective is understanding the role of Toll-like recep-

tors in the trophoblast and its interaction with the

maternal immune system. Together with this fund-

ing came the invitation from Dr. Yoshinaga to join

the Collaborative Team.

My participation in the Team meetings has proven

to be one of the most productive, educational, and

scientific encounters I have experienced. It has

exposed me to many new scientific aspects that I

was not familiar with, therefore expanding our

understanding of the field. The constructive critiques

of the Team members have been invaluable in help-

ing us to review our data and focus our studies in a

more productive manner.

Additionally, the meetings allowed me to establish

new collaborative work that otherwise would have

been impossible.

On a personal level, it provided me the opportu-

nity to meet leaders in the field with a high commit-

ment for mentorship, translational research, and

academic dedication.

Under the same umbrella, each of the members of

the Team brings a different aspect of expertise that

complements the scientific interests of the rest.

The continued participation of the members dur-

ing these years is a testimony to the high impact

that these activities have in our research. The com-

mitment of the NICHD to maintain and promote this

type of scientific activities will bring great benefit to

the science and the patients.

Soumen Paul (University of Kansas, Kansas City,

KS), member since 2010

I joined the Interdisciplinary Collaborative Team for

Blastocyst Implantation Research in 2010 after I got a

proposal from Dr. Koji Yoshinaga. The first meeting I

attended with the collaborative team is in October

2010. I joined this team mainly due to my scientific

interest. One major focus of my research is to under-

stand transcriptional mechanisms that regulate tro-

phoblast development. The development of

trophoblast cell lineages starts with the specification

of the trophectoderm (TE), one of the first two cell

lineages that are specified during pre-implantation

mammalian development. Studies in rodent models

indicate that, in early mammalian blastocyst, a few

trophectodermal cells are the trophoblast stem cell

(TSC) population, which give rise to differentiated

trophoblast subtypes upon subsequent development.

Interestingly, proper interaction between the TE and

the maternal tissue is essential for embryo implanta-

tion and improper TE specification results in either

impaired pre-implantation development or defective

embryo implantation, which are the leading causes

of early pregnancy failure. Thus, my research inter-

est is a major driving force behind joining the collab-

orative team.

The opportunity to join this group has immensely

helped me in two different aspects:

(i)Opportunities for Critical Scientific Learning: The

membership in the collaborative team has pro-

vided me an excellent opportunity for critical sci-

entific learning. Along with proper trophoblast

development, successful implantation of blast-

ocysts depends on multiple other factors, including

exquisite control of uterine receptivity and adapta-

tion of immune system at the maternal–fetalinterface. The collaborative team includes the

world leaders in these subject areas and my inter-

actions with them provide me the opportunity to

obtain a holistic view of the implantation process

and to ask complementary scientific questions.

(ii)Opportunities for Collaboration: Another benefit of

joining this collaborative group is successful

exploration of my research by establishing scien-

tific collaborations. The collaborative group mem-

bers utilize different model systems to study

implantation. Thus establishing collaboration has

provided me opportunity to readily test my scien-

tific findings in multiple mammalian systems.

As I indicated above, I have tremendously bene-

fited after joining the team. I successfully established

collaboration with other team members and we have

been able to publish our research together. In near

future, I plan to establish more collaboration and to

apply for joint research funding. If I get the opportu-




nity, I will always be a part of this type of collabora-

tive team.

Xiaoqin Ye (University of Georgia, Athens, GA)

member since 2011

What made you join the Team? I ‘accidentally’ entered

the research area in embryo implantation when I

was studying Lpar3-deficient mice in Dr. Jerold

Chun’s neuroscience-oriented laboratory. The first

paper about defective implantation in Lpar3-deficient

mice was published in 2005. I started my own labo-

ratory in August 2007 and continued on implanta-

tion research. On September 5th, 2007, I came

across the newly published PA-07-445 [Interdisci-

plinary Research on Implantation (R01)]. It was a

perfect match! It instantly became my goal to obtain

an R01 grant under this PA and join the team! Thisgoal was finally and gratefully achieved four years

later! Originally, it was the research focus that

attracted me the most to join the team. After becom-

ing a team member, I have realized more benefits to

be part of the team.

What benefit did you get by joining the Team?

(i)The prerequisite R01 grant keeps our research

active.

(ii)The team meetings serve as checkpoints to keep

our research focused and on track because every

member has to report on research progress at the

team meetings.

(iii)Every member has a unique niche on embryo

implantation research. The team meetings pro-

vide an indispensable opportunity for us not only

to be updated with the latest findings associated

with embryo implantation but also to understand

embryo implantation process from different

angles.

(iv)We receive insightful comments/suggestions from

the team members and experts in the field. The

multidisciplinary discussions surrounding the

embryo implantation process at the team meet-

ings are inspiring for every member’s research.

(v)The team meetings effectively promote collabora-

tions.

(vi)Dr. Koji Yoshinaga and Dr. Mercy PrabhuDas

have been great resources for our research.

What is your future perspective of this mechanism? This

mechanism has been working wonderfully for our

Team. I think the keys for this mechanism to be suc-

cessful are: (i) to keep the research topic well

focused on a unique topic, (ii) to keep the group

small (<20 members?) so that there will be effective

and efficient interactions among the members during

<2-day meeting, (iii) to have a dedicated and enthu-

siastic director (like Dr. Yoshinaga), and (iv) to have

every member’s full participation.

Sudhansu K. Dey (Cincinnati Children’s Hospital

Medical Center, Cincinnati, OH) member since

2011

I joined the Interdisciplinary Collaborative Team for

Blastocyst Implantation Research for a variety of rea-

sons. First, joining this team allowed me access to

diverse knowledge within the field, to meet new

people and be exposed to new ideas, and to both

present our work to other researchers as well as

learn about their research. In addition, in order to

keep the field growing and thriving I find it neces-

sary to engage in vigorous discussion about how to

take the field to the next level. Thus, it was my hope

that this group would be able to steer the future of

research forward together. After joining the Team, I

was pleased to find all of the above.

As we must continuously improve in order to pre-

vent stagnation, I believe the Team can best be

served by people working together collaboratively to

enrich the available resources in order to address

common biological causes. Additionally, it is very

important for critical but constructive discussions on

one’s own and other’s research. Failing to work

together to improve our studies can very quickly

lead to subpar findings and poor information. The

Team’s future prospects lie in its ability to expose

junior investigators to diverse views and animal

models within the field of implantation biology.

Such exposure is highly important for junior

researchers as it will allow them to gain a better per-

spective on their own research, a much broader

vision of the field, and an understanding of the his-

tory of the field as a whole. In addition, it will pres-

ent opportunities for them to collaborate with others

in new and exciting ways. Finally, it was very

important to meet with NICHD officials directly to

keep up with the changing rules and guidelines of

the NIH system.

The major difference between the U01 versus this

collaborative program is that the U01 grant structure

puts an additional financial burden on the granting

institute because it requires initial peer review of all

applications as well as administrative costs. Mean-




while, investigators in the collaborative program

come together through the normal competing R01

system, therefore allowing the NIH to save money.

However, one concern is that the group may become

too large and thus dysfunctional, whereas the num-

ber of investigators is quite limited in the U01

program.

Thomas Spencer (Washington State University,

Pullman, WA) member since 2012

What made you join the team? I joined the team in

order to intellectually leverage my current R01

funding by using the intellectual resources of similar

grants that are funded in the area of blastocyst

implantation. This type of team approach to science

is not available through other extramural agencies

or reproductive biology societies.

What benefit did you get by joining the team? By pre-

senting my most current research findings to a

diverse group of scientists working in a similar area

with different model systems, I can leverage and

expand my findings in terms of their application and

relevance to implantation biology at the basic and

translational levels. In addition, the wide expertise

of the team members will strengthen current and

future research projects and directions.

What is your future perspective of this mechanism? This

mechanism is a cost-effective approach to help

investigators funded by the NIH seek each other out

and begin to collaborate in a physical or intellectual

manner. There are many positive aspects. The nega-

tive aspects are the lack of funds for travel to the

annual team member meeting. Perhaps, this meeting

could be held in conjunction with Society for the

Study of Reproduction or Society for Gynecologic

Investigation or perhaps the new Gordon Research

Conference. In summary, the positive aspects out-

weigh the negative for the collaborative teams in my

opinion.

R. Michael Roberts (University of Missouri,

Columbia, MO) member since 2013

Why did I join the team? There are two main rea-

sons. The first is that for several years I chaired the

meetings of the old implantation group. I found

those meetings stimulating and informative, and

hence worth my while attending. I decided to apply

to the new team because it still contains some old

colleagues but also additional younger scientists

whom I consider up-and-coming. I hope that I can

be helpful to them and that they continue to pro-

vide ideas to me.

As indicated above, I am hoping to find the meet-

ings informative and stimulating. An additional ben-

efit will be to establish collaborations. Although

these are not assured, remarkably productive

outcomes can arise from unexpected sources.

I regard this sort of meeting as providing an inten-

sive, focused 2 days of information sharing and net-

working that is rarely matched at a standard

scientific meeting. Moreover, the cost of attending is

relatively modest.

References

1 PA-07-445: Interdisciplinary Research on Implantation (R01). NIH

official publication 2007.

2 Yoshinaga K: Directions of research on immune aspects of Blastocyst

Implantation Essential Factors (BIEFs). In Translational Research in

Uterine Biology, T Maruo, H Mardon, C Stewart (eds). Amsterdam,

Elsevier, 2008, pp 149–158.

3 Home P, Saha B, Ray S, Dutta D, Gunewardena S, Yoo B, Pal A,

Vivian JL, Jarson M, Petroff M, Gallagher PG, Schulz VP, White KL,

Golos TG, Behr B, Paul S: Altered subcellular localization of

transcription factor TEAD4 regulates first mammalian cell lineage

commitment. Proc Natl Acad Sci USA 2012; 109:7362–7367.

Koji Yoshinaga1, Mercy PrabhuDas2, Christopher

Davies3, Kenneth White3, Kathleen Caron4, Thaddeus

Golos5, Asgerally Fazleabas6, Bibhash Paria7, Gil Mor8,

Soumen Paul9, Xiaoqin Ye10, Sudhansu K. Dey11,

Thomas Spencer12, Robert Michael Roberts13

1Fertility and Infertility Branch, NICHD, NIH, DHHS,

Bethesda, MD, USA2Basic Immunology Branch, NIAID, NIH, DHHS,

Bethesda, MD, USA3Animal, Dairy and Veterinary Sciences Department,

College of Agriculture, Utah State University, Logan,

UT, USA4Department of Cell and Molecular Physiology, Univer-

sity of North Carolina, Chapel Hill, NC, USA5Departments of Comparative Biosciences and Obstet-

rics and Gynecology, University of Wisconsin, Madison,

WI, USA6Department of Obstetrics, Gynecology & Reproductive

Biology, College of Human Medicine, Michigan State

University, Grand Rapids, MI, USA7Department of Pediatrics/Neonatology, School of Med-

icine, Vanderbilt University, Nashville, TN, USA




https://www.researchgate.net/publication/224824948_Altered_subcellular_localization_of_transcription_factor_TEAD4_regulates_first_mammalian_cell_lineage_commitment?el=1_x_8&enrichId=rgreq-f9155fff8dc8540d846d02d8098c569e-XXX&enrichSource=Y292ZXJQYWdlOzI1OTAwMTUwMDtBUzoxNDE2MjY2Mzg4Njg0ODBAMTQxMDc3NzgzMDc1OA==





https://www.researchgate.net/publication/44585797_Research_on_Blastocyst_Implantation_Essential_Factors_BIEFs?el=1_x_8&enrichId=rgreq-f9155fff8dc8540d846d02d8098c569e-XXX&enrichSource=Y292ZXJQYWdlOzI1OTAwMTUwMDtBUzoxNDE2MjY2Mzg4Njg0ODBAMTQxMDc3NzgzMDc1OA==




8Department of Obstetrics, Gynecology and Reproduc-

tive Sciences, School of Medicine, Yale University, New

Haven, CT, USA9Institute for Reproductive Biology and Medicine, Uni-

versity of Kansas Medical Center, Kansas City, KS, USA10Department of Physiology and Pharmacology, Univer-

sity of Georgia, Athens, GA, USA11 Department of Reproductive Sciences, Cincinnati Chil-

dren’s Hospital Medical Center, Cincinnati, OH, USA12Department of Animal Sciences, Washington State

University, Pullman, WA, USA

13 Life Sciences Center, University of Missouri,

Columbia, MO, USA

Correspondence

Koji Yoshinaga, Fertility and Infertility Branch, NICHD,

NIH, DHHS, Bldg 6100, Room 8B01, Bethesda, MD

20892-7510, USA.

E-mail: [email protected]

doi: 10.1111/aji.12173




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