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.

项目概要早孕流产是最常见的早孕并发症，其发生率估计为〜75%，描述植入周围和植入后过程的机制将有助于减少这种不利影响。妊娠结局，蜕膜化，基质细胞增殖和分化形成的过程。蜕膜，支持胚胎从着床后到胎盘前的生长和存活。细胞外基质（ECM）重塑和血管生成是与细胞外基质（ECM）平行发生的潜在事件。纤维状胶原蛋白是主要的 ECM 蛋白质组，在蜕膜中含量丰富，然而，它们在子宫内膜蜕膜化、胚胎侵袭和发育中的作用。我们的初步数据表明，纤维状胶原蛋白经历了戏剧性的变化。与非蜕膜化的植入前子宫内膜相比，蜕膜内的重塑。小鼠模型中，我们提供了令人信服的证据，证明纤维状胶原蛋白在 Col5a1（V 型胶原蛋白 α1 链）的条件性缺失。由于严重的宫内出血和胚胎完全吸收，导致完全妊娠失败。根据这些强有力的初步数据，我们建议描述子宫内膜蜕膜化的缺陷和胚胎侵入，导致缺乏 Col5a1 的子宫中胚胎完全吸收（目标 1），表征 Col5a1 介导的纤维胶原重塑决定蜕膜化和胚胎的进展生长（目标 2），并确定受损的血管生成和破坏的血管重塑是主要的潜在因素导致 Col5a1 条件性敲除小鼠宫内出血的机制（目标 3）。生理相关且新颖的体内模型 – 子宫特异性 Col5a1 条件敲除小鼠 – 我们还将利用纤维状胶原在子宫内膜蜕膜化和血管生成中的功能。包括成像技术和体外细胞衍生基质在内的方法的独特组合。这项研究的结果将增强我们对子宫内膜过程中纤维状胶原蛋白功能的理解蜕膜化和血管生成。