Tissue Factor and Emdometriosis

组织因子和子宫内膜异位症

• 批准号: 7318129
• 负责人: CHARLES JOSEPH LOCKWOOD
• 金额: $ 28.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318129
• 关键词: Accounting; Activated Natural Killer Cell; Adhesions; Agonist; Angiogenic Factor; Apoptosis; Binding; Blood Coagulation Factor VII; Cell Line; Cells; Conditioned Culture Media; Coupled; Disease; Endometrial; Endometrium; Endopeptidases; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Etiology; Factor Xa; Focal Adhesions; Gene Expression; Gland; Growth; Hemorrhage; Human; Immunoconjugates; Immunoglobulin G; Immunotherapy; Implant; Incubated; Infertility; Infiltration; Inflammation; Inflammatory; Integrins; Interleukin-8; Interleukins; Malignant - descriptor; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metaplasia; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Mus; Mutate; Natural Killer Cells; Numbers; Ovarian; PAR-2 Receptor; Pain; Pathogenesis; Pathway interactions; Patients; Pelvis; Peptide Hydrolases; Production; Proteins; Reactive Oxygen Species; Recruitment Activity; Reporting; Retrograde Menstruation; Reverse Transcriptase Polymerase Chain Reaction; Role; SCID Mice; Signal Transduction; Staging; Steroids; Stromal Cells; Testing; Thromboplastin; Time; Tissues; Transplantation; Tube; Uterine cavity; Vascular Endothelial Growth Factors; Woman; angiogenesis; base; cell motility; cytokine; endometriosis; immortalized cell; laser capture microdissection; macrophage; mouse model; natural Blastocyst Implantation; novel; prevent; protein expression; receptor; response

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.

子宫内膜异位症是由子宫外子宫内膜植入引起的盆腔粘连，出血， 不孕症和疼痛假体植入的长期存活与显著的局部 炎症、剧烈的血管生成和组织因子（TF）的过度表达。在一些恶性和 在炎症状态下，TF与因子Vila结合，激活2型蛋白酶激活受体（PAR-2）以上调 炎症细胞因子、基质金属蛋白酶（MMP）和血管内皮细胞的表达 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 我们假设肿瘤组织的着床、生长和血管生成的基础是 子宫内膜细胞和浸润巨噬细胞TF表达增强。因子VII的后续结合 TF激活PAR-2以诱导血管生成、蛋白水解和炎症介质的表达。的 后者反过来诱导PAR-2和血管生成因子受体在相邻内皮细胞中的表达 来产生一种强有力的血管生成反应。一种新的免疫缀合物分子（ICON），其包含两个 突变的因子VII结构域和IgG Fc效应器结构域，靶向TF，同时还募集活化的天然 杀伤（NK）细胞。初步结果还表明，ICON阻断生长和血管生成， 表达TF的人子宫内膜上皮细胞系移植到严重联合免疫缺陷的小鼠体内 小鼠（SCID）。考虑到过度表达的TF在肿瘤的形成和生长中的重要性， 植入物，我们认为ICON治疗将根除乳房植入物。为了验证这些假设，我们 本研究的具体目的是：1）研究TF和PAR-2在人肝癌细胞中的表达和定位， 子宫内膜异位症患者的在位和异位子宫内膜; 2）评估子宫内膜异位症的分子途径 TF/VIIa/PAR-2信号在子宫内膜上皮细胞、间质细胞和巨噬细胞中的作用 这种信号传导对内皮细胞迁移、增殖、管形成和凋亡的影响;以及3） 确定在小鼠模型中用ICON治疗是否根除了肿瘤植入物。这些研究 检查原始的致病模型，以解释肿瘤植入物的存活和增殖 并评估一种新的，无毒的治疗方法，可以消除植入的肿瘤。