The innate immune system represents an important cellular component at the maternal-fetal interface and it is critical for the survival of the fetus. Our overall hypothesis is that the innate immune system is necessary for normal pregnancy by supporting i) trophoblast implantation/invasion, ii) vascularization and iii) host protection. We propose that the cellular component at the implantation site communicate with each other throughout a network of cytokines/chemokines. Such crosstalk occurs through the expression of specific receptors, known as Toll-Like Receptors (TLRs), which may direct and coordinate this cytokine/chemokine network. Our central hypothesis is that TLRs expressed at the maternal-fetal interface serve as sensors for the recognition and response to the environment throughout implantation and gestation. Our main goal is to determine and characterize the specific role of TLRs during pregnancy. In this program application, three groups of investigators from the Department of Obstetrics, Gynecology and Reproductive Sciences at Yale University School of Medicine will evaluate the role of TLRs in the interactions between trophoblast cells, decidual cells (stromal/endothelial) and innate immune cells. Furthermore, the program will investigate the role of TLRs in, trophoblast invasion, spiral artery transformation and host protection during the first trimester of pregnancy and at term. The three groups have extensive experience in placental/uterine biology and reproductive immunology. In Project I. (Mor/Abrahams) will test the hypothesis that the trophoblast controls the presence and function of the innate immune system at the implantation site by responding to the maternal environment through the expression of TLRs. Project II. (Lockwood/Krikun) will test the hypothesis that the activation of TLRs expressed by decidual stromal and innate immune cells plays a role in promoting trophoblast invasion and transformation of spiral arteries. Project III. (Guller/Norwitz) will test the hypothesis that cross-talk between TLR and GR-dependent signaling pathways in placental syncytiotrophoblast (SCT) and fibroblasts (FIBs) protects the fetus against microbial compounds while limiting inflammation at this site.

Public Health Relevance

The results of these studies will provide a entirely new perception on the interactions between the maternal immune system, the decidua and the trophoblast;and will provide new insight for the development of novel therapeutic approaches for pregnancy complications

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD054713-04
Application #
8280173
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (GM))
Program Officer
Yoshinaga, Koji
Project Start
2009-06-10
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$1,054,061
Indirect Cost
$417,166
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hoang, Mai; Potter, Julie A; Gysler, Stefan M et al. (2014) Human fetal membranes generate distinct cytokine profiles in response to bacterial Toll-like receptor and nod-like receptor agonists. Biol Reprod 90:39
Dekel, Nava; Gnainsky, Yulia; Granot, Irit et al. (2014) The role of inflammation for a successful implantation. Am J Reprod Immunol 72:141-7
Aldo, Paulomi B; Racicot, Karen; Craviero, Vinicius et al. (2014) Trophoblast induces monocyte differentiation into CD14+/CD16+ macrophages. Am J Reprod Immunol 72:270-84
Racicot, Karen E; W√ľnsche, Vera; Auerbach, Ben et al. (2014) Human chorionic gonadotropin enhances trophoblast-epithelial interaction in an in vitro model of human implantation. Reprod Sci 21:1274-80
Racicot, Karen; Kwon, Ja-Young; Aldo, Paulomi et al. (2014) Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol 72:107-16
Kwon, Ja-Young; Romero, Roberto; Mor, Gil (2014) New insights into the relationship between viral infection and pregnancy complications. Am J Reprod Immunol 71:387-90
Bakaysa, S L; Potter, J A; Hoang, M et al. (2014) Single- and double-stranded viral RNA generate distinct cytokine and antiviral responses in human fetal membranes. Mol Hum Reprod 20:701-8
Abrahams, Vikki M; Potter, Julie A; Bhat, Geeta et al. (2013) Bacterial modulation of human fetal membrane Toll-like receptor expression. Am J Reprod Immunol 69:33-40
Racicot, Karen; Cardenas, Ingrid; Wunsche, Vera et al. (2013) Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol 191:934-41
Krikun, Graciela; Potter, Julie A; Abrahams, Vikki M (2013) Human endometrial endothelial cells generate distinct inflammatory and antiviral responses to the TLR3 agonist, Poly(I:C) and the TLR8 agonist, viral ssRNA. Am J Reprod Immunol 70:190-8

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