Endometriosis results from extrauterine endometrial implants that cause pelvic adhesions, bleeding, infertility, and pain. Long-term survival of endometriotic implants is associated with marked local inflammation, vigorous angiogenesis and over-expression of tissue factor (TF). In a number of malignant and inflammatory states, TF bound to factor Vila, activates the type-2 protease activated receptor (PAR-2) to upregulate the expression of inflammatory cytokines, matrix metalloproteinases (MMP) and vascular endothelial growth factor (VEGF) to promote cell invasion and angiogenesis. Novel Preliminary Results form the basis of our hypothesis that nidation, growth and angiogenesis of endometriotic tissue results from enhanced TF expression in endometrial cells and infiltrating macrophages. Subsequent binding of factor VII to TF activates PAR-2 to induce expression of angiogenic, proteolytic and inflammatory mediators. The latter, in turn, induce expression of PAR-2 as well as angiogenic factor receptors in adjacent endothelial cells to generate a potent angiogenic response. A novel immunoconjugate molecule (ICON) comprised of two mutated factor VII domains and an IgG Fc effector domain, targets TF while also recruiting activated Natural Killer (NK) cells. Preliminary Results also demonstrate that ICON blocks the growth and angiogenesis in a TF-expressing human endometrial epithelial cell line transplanted into severe combined immunodeficient mice (SCID). Given the integral importance of over-expressed TF in the nidation and growth of endometriotic implants, we posit that ICON treatment will eradicate endometriotic implants. To test these hypotheses we propose the following Specific Aims: 1) To characterize the expression and localization of TF and PAR-2 in eutopic and ectopic endometrium from endometriosis patients; 2) To assess the molecular pathway(s) of TF/Vlla/PAR-2 signaling in endometrial epithelial and stromal cells, and macrophages as well as the effects of such signaling on endothelial cell migration, proliferation, tube formation and apoptosis; and 3) to determine if treatment with ICON eradicates endometriotic implants in a murine model. These studies examine an original pathogenic model to account for the survival and proliferation of endometriotic implants and evaluate a novel, non-toxic therapy that could eradicate endometriotic implants.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD052668-02
Application #
7656584
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2008
Total Cost
$318,368
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Liu, Ying; Tal, Reshef; Pluchino, Nicola et al. (2018) Systemic administration of bone marrow-derived cells leads to better uterine engraftment than use of uterine-derived cells or local injection. J Cell Mol Med 22:67-76
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Pluchino, Nicola; Mamillapalli, Ramanaiah; Moridi, Irene et al. (2018) G-Protein-Coupled Receptor CXCR7 Is Overexpressed in Human and Murine Endometriosis. Reprod Sci 25:1168-1174
Sahin, Cagdas; Mamillapalli, Ramanaiah; Taylor, Hugh S (2018) Bone Marrow-Derived Cells Trafficking to the Oviduct: Effect of Ischemia-Reperfusion Injury. Reprod Sci 25:1037-1044
Moridi, Irene; Mamillapalli, Ramanaiah; Cosar, Emine et al. (2017) Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis. Reprod Sci 24:526-533
Naqvi, Hanyia; Mamillapalli, Ramanaiah; Krikun, Graciela et al. (2016) Endometriosis Located Proximal to or Remote From the Uterus Differentially Affects Uterine Gene Expression. Reprod Sci 23:186-91
Flannery, Clare A; Saleh, Farrah L; Choe, Gina H et al. (2016) Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma. J Clin Endocrinol Metab 101:2883-91
Flannery, Clare A; Fleming, Andrew G; Choe, Gina H et al. (2016) Endometrial Cancer-Associated FGF18 Expression Is Reduced by Bazedoxifene in Human Endometrial Stromal Cells In Vitro and in Murine Endometrium. Endocrinology 157:3699-3708
Kulp, Jennifer L; Mamillapalli, Ramanaiah; Taylor, Hugh S (2016) Aberrant HOXA10 Methylation in Patients With Common Gynecologic Disorders: Implications for Reproductive Outcomes. Reprod Sci 23:455-63

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