Extracellular Matrix-Mediated Endometrial Decidualization and Angiogenesis

细胞外基质介导的子宫内膜蜕膜化和血管生成

基本信息

批准号：
10635013
负责人：
Shanmugasundaram Nallasamy
金额：
$ 46.67万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10635013
关键词：
Architecture Biological Assay Blood Vessels Cell Differentiation process Cell Proliferation Cells Collagen Collagen Fiber Collagen Type V Data Decidua Decidual Cell Reactions Defect Development Dissection Ehlers-Danlos Syndrome Electron Microscopy Electrons Elements Embryo Embryo Resorption Endometrial Endometrial Stromal Cell Endometrium Endothelial Cells Epithelium Event Exhibits Extracellular Matrix Extracellular Matrix Proteins Failure Fibrillar Collagen First Pregnancy Trimester Functional disorder Generations Goals Growth Hemorrhage Human Hypoxia Imaging Techniques Impairment In Vitro Incidence Invaded Knockout Mice Link Literature Maternal-Fetal Exchange Mediating Morphology Mus Mutation Natural Killer Cells Outcome Outcome Study Physiological Placenta Placentation Play Pregnancy Pregnancy Complications Prevention Process Proliferating Proteins Publishing Reporting Role Signal Pathway Stromal Cells Structure Tissues Uterine hemorrhage Uterus Vascular Endothelial Growth Factors Vascular Permeabilities Vascular remodeling Woman Zebrafish adverse pregnancy outcome angiogenesis clinically significant conditional knockout confocal imaging design early pregnancy early pregnancy loss failure Implantation implantation improved in vivo in vivo Model mechanotransduction microscopic imaging mortality mouse model natural Blastocyst Implantation novel pregnancy failure preimplantation public health relevance response second harmonic second harmonic generation imaging success tool trophoblast

项目摘要

Project Summary Early pregnancy loss is the most prevalent early pregnancy complication, and its incidence is estimated to be ~75%. Thus, delineating the mechanisms of peri and post-implantation processes will help reduce this adverse pregnancy outcome. Decidualization, a process of stromal cell proliferation and differentiation for the formation of decidua, supports embryonic growth and survival from post-implantation through pre-placentation period. Extracellular matrix (ECM) remodeling and angiogenesis are underlying events that occur in parallel to the decidualization. Fibrillar collagens are predominant ECM group of proteins which are abundant in the decidua, endothelial cells, and vascular wall. However, their role in the endometrial decidualization, embryo invasion and angiogenesis are not known. Our preliminary data suggests that the fibrillar collagen undergoes dramatic remodeling within the decidua compared to non-decidualized pre-implantation endometrium. Utilizing a novel mouse model, we provide compelling evidence that the fibrillar collagen is playing an indispensable role in endometrial decidualization and angiogenesis. Conditional deletion of Col5a1 (collagen type V alpha 1 chain) resulted in complete pregnancy failure due to severe intrauterine hemorrhage and total embryo resorption. Based on these strong preliminary data, we propose to characterize the defects in endometrial decidualization and embryo invasion which lead to total embryo resorption in the uterus lacking Col5a1(aim 1), characterize the Col5a1-mediated fibrillar collagen remodeling that determines progression of decidualization and embryonic growth (aim 2), and identify impaired angiogenesis and disrupted vascular remodeling as predominant underlying mechanisms that cause intrauterine hemorrhage in Col5a1 conditional knockout mice (aim 3). We will utilize a physiologically relevant and novel in vivo model – uterine specific Col5a1 conditional knockout mice – to interrogate the function of fibrillar collagen in endometrial decidualization and angiogenesis. We will also utilize a unique combination of approaches including imaging techniques and in vitro cell derived matrices. The outcomes of this study will enhance our understanding on the function of fibrillar collagen during endometrial decidualization and angiogenesis.

项目摘要早期怀孕丧失是最普遍的早期妊娠并发症，据估计其事件是〜75％。这就是描述春季和植入后过程的机制，将有助于减少这种对手怀孕结果。 deDializatization，基质细胞增殖的过程和形成的分化在决定性的情况下，支持胚胎生长和从植入后到定位期的生存。细胞外基质（ECM）重塑和血管生成是与之平行发生的基本事件决定性化。原纤维胶原蛋白是主要的ECM蛋白质，在决策中很丰富，内皮细胞和血管壁。但是，它们在内部测量决定性化，胚胎侵袭和血管生成尚不清楚。我们的初步数据表明，纤维状胶原蛋白会发生戏剧性与非角化植入前子宫内膜相比，Chineua内的重塑。利用小说鼠标模型，我们提供了令人信服的证据，表明纤维胶原蛋白在子宫内膜决定和血管生成。有条件删除Col5a1（胶原型V alpha 1链）由于严重的内部出血和总胚胎分辨率，导致妊娠失败。基于在这些强大的初步数据上，我们建议表征子宫内膜决定性的缺陷和胚胎入侵导致缺乏COL5A1的子宫中总胚胎分辨率（AIM 1） COL5A1介导的原纤维胶原蛋白重塑，该胶原蛋白决定决定性化和胚胎的进展生长（AIM 2），并确定血管生成受损并破坏血管重塑为主要基础在COL5A1有条件敲除小鼠中引起宫内出血的机制（AIM 3）。我们将利用一个生理相关和新颖的体内模型 - 子宫特异性COL5A1条件敲除小鼠 - 询问原纤维胶原蛋白在子宫内膜决定和血管生成中的功能。我们还将利用包括成像技术和体外细胞衍生物质在内的一种独特的方法组合。这这项研究的结果将增强我们对子宫内膜纤维胶原功能功能的理解义词化和血管生成。