Project I

Role of Toll-like receptors in trophoblast immune regulation

Toll-like Receptors (TLRs) mediate trophoblast recognition of the uterine microenvironment that under normal conditions contain commensal microbes and stress proteins, and respond to it by recruiting a large number of immune cells, such as macrophages, natural killer (NK) cells and regulatory T cells (Treg), all found in the decidua. The appropriate communication between all these cellular components at the maternal-fetal interface is crucial for successful reproduction. TLRs expressed by the trophoblast function as sensors which induce the production of cytokines/chemokines that will in turn regulate immune cell distribution and function at the maternal-fetal interface. However, if the function of TLRs is left unchecked, the maternal-fetal interface may become overwhelmed by immune activation. Therefore, TLR function and signaling must be tightly regulated in order to prevent pathological conditions.

The studies of Project I evaluate the supportive regulatory interactions between first trimester trophoblasts and the maternal immune system. They also investigate the role of Toll-like Receptors (TLR) in these processes. The objectives of Project I are to:

  • Understand TLR function in first trimester trophoblast cells
  • Determine the effects of trophoblast TLR activation on maternal immune cells
  • Characterize regulatory mechanisms controlling TLR expression and function at the maternal-fetal interface
  • Evaluate the role of TLRs in pregnancy outcome 

Aim I: Determine cytokine profile in first trimester trophoblast cells following TLR ligation.;
As trophoblast express TLR's on their cell surface, they are able to recognize and respond to endogenous lignads present in the microenvironment. This aim elucidates the effect of endogenous ligands on TLR-4 induced cytokine response and survival in trophoblast cells; TLR-mediated production of antimicrobial factors by trophoblast cells and the role of estrogen on the regulation of TLR expression and function;

Aim II: Characterize the effect of trophoblast TLR activation on immune cell recruitment and function.

Differentiation and function of immune cells infiltrating the implantation site depends, largely in part, on the microenvironment created by the placenta. Trophoblast cells can induce the differentiation of immune cells into trophoblast-supporting phenotype. This aim will determine what is the phenotype and function of monocytes differentiated by trophoblast cells as well as the effect of trophoblast cells on T-cell differentiation and activation 

Aim III: Study the regulation of TLR expression and function in trophoblast cells.

Excessive activation or dampened responses of TLRs may lead top pathological conditions. Therefore, TLR signaling in trophoblast cells must be under tight regulation.  Aim III focuses on the role of IKKb in the regulation of trophoblast responses to stimulation by TLR-4 or TLR-3 ligands and the role of cytokines on the function of intracellular regulators of the TLR-3 and TLR-4 pathways 

Aim IV: In vivo studies for the characerization of TLR function in pregnancy.

TLRs expressed on trophoblast coordinate the maternal immune response towards pathogens and an abnormal immune response may lead to pregnancy failure. In order to dissect the role of fetal vs. maternal TLR during implantation and pregnancy, we use embryo transfer of wild-type and TLR-deficient mice to determine the role of both maternal and fetal TLR responses.

Publications

Publications (2007-present)
Papers in preparation
Presentations at meetings

  1. Fest S., Aldo P.B., Abrahams V., Visintin I., Alvero A., Chen R., Chavez S., Romero R. and Mor G. (2007) Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy. American Journal of Reproductive Immunology: 57(1):55-66.
  2. Chen R,. Ayesha A B, Silasi D-A, Mor G (2007) Inflammation, Cancer and Chemoresistance: Taking Advantage of the Toll-Like Receptor Signaling Pathway. American Journal of Reproductive Immunology. 57(2):93-107
  3. Kluger, H., McCarthy, M., Alvero, A., Sznol, M., Halaban, r., Camp, RL., Rimm, D., Mor, G. (2007)The X-linked inhibitor of apoptosis protein (XIAP) is up-regulated in metastatic melanoma and is associated with chemotherapy resistance Journal of Translational Medicine. 26;5(1):6
  4. Agarwal R, Alvero A., Visentin I, Lai Y, Schwartz P., Rutherford, T., Ward D. and Mor G. (2007) Macrophage Migration Inhibitory Factor expression in ovarian cancer. American Journal of Obstetrics and Gynecology 196(4):348.e1-5
  5. Chavez, S., Visintin, I., Karassina, N., Los, G., Liston, P., Halaban, P., Fadiel, A., Mor G.  (2007) Xaf1 Mediates Tnf-Alpha-Induced Apoptosis And Xiap Cleavage By Acting Through The Mitochondrial Pathway.  The Journal of Biological Chemistry.  282 (17): 13059-13072
  6. Alvero . A., Brown D. Montagna, M., Matthews, M., Mor, G.(2007) Phenoxodiol-Topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects. Cancer Biology and Therapy: 6 (4): e1-e6
  7. Silasi, D. Illuzzi, JL., Kelly, M., Rutherford, T., Mor, G., Azodi, M., Schwartz, PE (2007) Carcinoma of the ovary. International Journal of Cancer:  April 19 on line
  8. Krikun, G., Lockwood, C.J., Abrahams, V.M., Mor, G., Paidas, M., Guller, G.. Expression of Toll-like receptors in the human decidua. Histology and Histopathology 2007: 22(8):847-54.
  9. Ma, Y.Y., Krikun, G., Abrahams, V.M., Mor, G., Guller, S.. (2007) Cell Type-Specific Expression and Function of Toll-Like Receptors 2 and 4 in Human Placenta. Placenta: 8: 1024-1031
  10. Aldo, P., Krikun, G., Visintin, I., Lockwood, C., Romero, R., Mor, G. (2007) A Novel Three-Dimensional In Vitro And In Vivo System To Study Trophoblast–Endothelium Cell Interactions.  American Journal of Reproductive Immunology: 58(2): 98-110
  11. Koga, K. and Mor G. (2007) Toll-Like Receptors and Pregnancy. Reproductive Sciences14: 297-301
  12. Silasi, D., Alvero, A., Illuzi, J. Kelly, M., Chen, R., Fu, H., Schwartz, P., Rutherford, T., Azodi, M., Mor, G. (2007)  MyD88 predicts chemoresistance to paclitaxel in epithelial ovarian cancer.  Yale Journal of Biology and Medicine 79(3-4):153-63
  13. Hudson ME, Pozdnyakova I, Haines K, Mor G, Snyder M. (2007) Identification of differentially expressed proteins in ovarian cancer using high-density protein microarrays. Proc Natl Acad Sci U S A. Oct 22
  14. Smith, S., Su, D., Schwartz, P., Rutherford, T., Mor, G., Puopolo, M., Rigault de la Longrais, I. A., Yu, H., Katsaros, D. (2007) ERCC1 SNP at codon 118 and mRNA expression in relation to ovarian cancer survival among patients treated with platinum-based chemotherapy with or without Taxol. Journal of Clinical Oncology: 20;25(33):5172-9.
  15. Fest, S. Brachwitz, N.,  Schumacher, A., Zenclussen, ML., Khan, F., Wafula, PO., Casalis, PA., , Fill, S., Costa, SD., Mor, G., Volk, HD., Lode1, HN., Zenclussen, AC. (2008) American Journal of Reproductive Immunology 59: 75-83
  16. Chen, R., Alvero, AB., Silasi, DA., Steffensen, KD., Mor, G. (2007)  Cancer take their Toll: The function and regulation of Toll Like Receptors in cancer cells.  Oncogene: 
  17. Plaks V., Birnberg, T, Berkutzki, T., Kalchenko, V., Mor, G, Dekel, N, Neeman, M and Jung, S. (2008) Uterine Dendritic cells are crucial for Decidua Formation during Embryo Implantation.  Science. In press
  18. Zhang, K., Wang, Q., Xie, Y., Mor, G., Sega, E., Low, PS., Huang, Y. (2008) Receptor-mediated delivery of siRNAs by tethered nucleic acid base-paired interactions. Journal of RNA.  In press
  19. Visintin, I., Alvero, A., Lai, Y., Tenthorey, J., Leiser, A., Flores, R., Rutherford, T., Schwartz, P., Ward, D.,  Mor, G. (2008) Diagnostic Markers For Early Detection Of Ovarian Cancer.  Clinical Cancer Research.  2008;14 (4) February 15, 2008.
  20. Guller, S., Ma, YY., Fu, H., Krikun, G., Abrahams, VM., Mor. G. (2008) The placental syncytium and the pathophysiology of preeclampsia and Intrauterine growth restriction: a novel assay to assess syncytial protein expression.New York Academy of Science:  in press
  21. Mor, G.(2008) Inflammation and Pregnancy: The role of TLRs in Trophoblast immune interaction. New York Academy of Science:  in press
  22. Kelly, M., Mor, G., Goss, G., Kelly, G., Quinn, M., O’Mally, D., Baker, L., McAlpine, J., Azodi, M., Schwartz, P., Rutherford, T. (2008) Phase II evaluation of phenoxodiol in combination with cisplatin or paclitaxel in women with a history of platinum/taxane refractory/resistant epithelial ovarian, fallopian tube or primary peritoneal cancers. Gynecologic Oncology: Submitted
  23. Chen, R., Alvero, A., Silasi, D., Kelly, M., Fest, S., Leiser, A., Schwartz, S., Rutherford, P., Visintin, I., Mor, G. (2008) Regulation of IKKb by mir-199 affects NF-kB activity in ovarian cancer cells.  Oncogene: Submitted
  24. Fraccaroli, L., Alfieri, J., Larocca, L., Calafat, M., Mor, G., Pérez Leirós, C., Ramhorst, R.  (2008) A potential tolerogenic immune mechanism by trophoblastic through the activation of chemokine-induced t cell death and t -regulatory cells modulation.  Journal of Immunology: Submitted
  25. Abrahams, VM., Aldo, P., Murphy, SP., Visintin, I., Romero, R., Sharma, S., Mor, G.  (2008) Tlr6 protects trophoblast cells from TLR2/TLR1 mediated apoptosis.  Human Reproduction: Submitted

Books

  • IMMUNOLOGY OF IMPLANTATION.  Editor: Gil MorMedical Intelligence Unit  Springer, LANDES Bioscience  2006
  • APOPTOSIS AND CANCER . Editors:  Gil Mor and Ayesha Alvero   Methods in Molecular Medicine.  Human Press.  2007 Vol. 414

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