Tissue Factor and Emdometriosis

子宫内膜异位症是由子宫内膜异位症引起的盆腔粘连，出血， 不孕不育和疼痛。子宫内膜异位植入物的长期存活率与局部显著相关 炎症、强烈的血管生成和组织因子(TF)的过度表达。在许多恶性和恶性疾病中 炎症状态，Tf与V1a因子结合，激活2型蛋白酶激活的受体(PAR-2)上调表达 炎性细胞因子、基质金属蛋白酶与血管的表达 内皮生长因子(VEGF)促进细胞侵袭和血管生成。新的初步结果表格 我们假设子宫内膜异位症组织的侵袭、生长和血管生成是由 子宫内膜细胞和浸润性巨噬细胞的组织因子表达增强。因子VII的后续结合 TO TF激活PAR-2，诱导血管生成、蛋白水解性和炎性介质的表达。这个 后者进而诱导邻近内皮细胞表达PAR-2和血管生成因子受体。 以产生强大的血管生成反应。一种新型的免疫偶联分子(ICON) 突变的第VII因子结构域和免疫球蛋白Fc效应域，靶向Tf，同时也招募激活的Natural 杀伤(NK)细胞。初步结果还表明，ICON抑制了血管的生长和新生 表达转铁蛋白的人子宫内膜上皮细胞株移植到重度联合免疫缺陷 小鼠(SCID)。鉴于过表达的转铁蛋白在子宫内膜异位症的发生和生长中的重要作用 我们假设ICON治疗将根除子宫内膜异位症植入物。为了检验这些假设，我们 目的：1)研究Tf和PAR-2在骨肉瘤中的表达和定位。 子宫内膜异位症患者在位和异位内膜；2)探讨子宫内膜异位症的分子途径(S) Tf/V11a/PAR-2信号在子宫内膜上皮细胞、间质细胞和巨噬细胞中的表达及其作用 这类信号在内皮细胞迁移、增殖、管状形成和凋亡中的作用；以及3) 在小鼠模型中确定ICON治疗是否能根除子宫内膜异位植入物。这些研究 检查原始致病模型以解释子宫内膜异位植入物的存活和增殖 评估一种新的、无毒的治疗方法，可以根除子宫内膜异位症植入物。

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.