Regulation of TGF-beta Receptor-dependent Vascular Disease

TGF-β 受体依赖性血管疾病的调节

基本信息

批准号：
7797526
负责人：
Calvin Pardee Hull Vary
金额：
$ 34.52万
依托单位：
MAINEHEALTH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-06 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7797526
关键词：
ACVRL1 gene Activins Address Adhesions Adhesives Adult Animal Model Animals Architecture Biochemical Biology Blood Vessels Cell Differentiation process Cell Proliferation Cell physiology Cytoskeletal Modeling Data Defect Devices Disease ENG gene Endoglin Endothelial Cells Event FVB Mouse Focal Adhesions Gene Targeting Genetic Goals Hereditary hemorrhagic telangiectasia Homeostasis Immigration In Vitro Knockout Mice LIM Domain Protein Laboratories Lead Length Ligands Maintenance Mediating Modeling Molecular Mus Pathology Pathway interactions Phenotype Phosphorylation Phosphotransferases Physiology Process Property Proteins Receptor Signaling Regulation Role Serine Signal Pathway Signal Transduction Smooth Muscle Myocytes TGF-beta type I receptor Telangiectasis Testing Threonine Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Transgenic Organisms Tube Vascular Diseases Wound Healing Yolk Sac ZYX gene activin receptor-like kinase 1 angiogenesis base biochemical model cell motility in vivo insight malformation mouse model mutant novel protein function protein protein interaction receptor response to injury

项目摘要

The long-term goal of this laboratory is to understand the processes by which endothelial cells (ECs) regulate vessel stability and homeostasis. Our focus is to understand the functional relationship between the TGF-beta receptor ALK1 and its co-receptor, endoglin. These molecules are important regulators of angiogenesis and wound healing, and are the target genes for the vascular disease hereditary hemorrhagic telangiectasia (HHT). We will test the hypothesis that endoglin transduces TGF-beta receptor signals in endothelial cells via a novel Smad-independent mechanism. Our studies demonstrate that endoglin is phosphorylated by ALK1, which we hypothesize regulates endoglin?s effects on focal adhesion re-organization, cytoskeletal architecture, and migration in ECs. To understand this novel endoglin signaling pathway and its relevance in the vasculature, the aims of this proposal are: Specific Aim 1: Examine the consequences of TGF-beta receptor-mediated phosphorylation of endoglin to determine how this pathway regulates EC function. Studies will focus on the role of putative protein-protein interactions mediated by endoglin?s cytosolic domain, emphasizing the regulation of EC focal adhesion assembly, tubulogenesis, TGF-beta receptor subcellular localization, and EC-specific intercellular signals. Specific Aim 2: Examine the consequences of EC-targeted expression of endoglin CD mutants in the yolk sac vasculature. This aim will emphasize cytosolic domain-dependent effects on EC tubulogenesis and angiogenic remodeling, and emphasize the endpoints used for Aim 1. The results obtained in these studies will elucidate the mechanism underlying endoglin?s regulation of intrinsic EC function as well as EC-initiated intercellular signals within the yolk sac vasculature in vivo. Specific Aim 3: Characterize the vascular abnormalities observed in the FVB:eng+/- mouse model. This aim builds on new preliminary data which suggests that the heterozygous eng+/- expressed on the FVB mouse genetic background constitutes a potentially novel and useful model of HHT vascular malformation. We will study the structural and biochemical properties of the FVB:eng+/- vasculature in order to understand the basis for its vascular malformations. This model will then be used to test whether EC-expressed transgenic endoglin is sufficient to rescue the vascular deficiencies. Our proposed mouse transgenic, genetic, and biochemical models of endoglin function will lead to a deeper understanding of novel mechanisms of TGF-beta receptor-dependent regulation of EC proliferation, adhesion, tubulogenesis, and angiogenic remodeling that culminate in the establishment and maintenance of vessel integrity. The proposed studies are highly relevant to normal vascular function, and will elucidate endoglin's role in adult-onset vascular diseases.

该实验室的长期目标是了解内皮细胞（ECS）调节血管稳定性和稳态的过程。我们的重点是了解TGF-β受体ALK1及其共受体endoglin之间的功能关系。这些分子是血管生成和伤口愈合的重要调节剂，并且是血管疾病遗传性出血性毛发性（HHT）的靶基因。我们将通过一种新型的独立于SMAD的机制来测试内og胶在内皮细胞中转导TGF-β受体信号的假设。我们的研究表明，内源于ALK1磷酸化，我们假设调节内og的影响对局灶性粘附重新组织的影响，细胞骨架结构和ECS中的迁移。为了理解这种新型的内聚糖信号通路及其在脉管系统中的相关性，该提案的目的是：特定目标1：检查TGF-beta受体介导的内og的后果，以确定该途径如何调节EC功能。研究将重点关注由内聚细胞胞质结构域介导的推定蛋白 - 蛋白质相互作用的作用，从而强调了EC粘着粘附组装，肾纤维生成，TGF-β受体亚细胞亚细胞定位和EC特异性细胞间信号的调节。具体目的2：检查蛋黄囊脉管系统中内o的CD突变体的EC靶向表达的后果。这个目标将强调胞质结构域依赖性对EC肾小管发生和血管生成重塑的影响，并强调用于AIM 1的终点。这些研究中获得的结果将阐明内og的基础机制的内在EC功能以及EC引起的EC启动的机制。蛋黄囊脉管系统内的细胞间信号。特定目标3：表征FVB中观察到的血管异常：ENG +/-小鼠模型。这个目标建立在新的初步数据的基础上，这表明在FVB小鼠遗传背景上表达的杂合ENG +/-构成了HHT血管畸形的潜在新颖且有用的模型。我们将研究FVB：ENG +/-脉管系统的结构和生化特性，以了解其血管畸形的基础。然后，该模型将用于测试EC表达的转基因内尾是否足以挽救血管缺陷。我们提出的内吞功能的小鼠转基因，遗传和生化模型将使对TGF-β受体依赖性调节EC增殖，粘附，微管发生和血管生成重塑的新机制有更深入的了解，从正直。拟议的研究与正常的血管功能高度相关，并将阐明内og在成人发作的血管疾病中的作用。