Regulation of TGF-beta Receptor-dependent Vascular Disease

TGF-β 受体依赖性血管疾病的调节

• 批准号: 7448001
• 负责人: Calvin Pardee Hull Vary
• 金额: $ 2.69万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-06 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7448001
• 关键词: ACVRL1 gene; Activins; Address; Adhesions; Adhesives; Adult; Animal Model; Animals; Appendix; Architecture; Biochemical; Biology; Blood Vessels; Cell Differentiation process; Cell Proliferation; Cell physiology; Cytoskeletal Modeling; Data; Defect; Depth; Devices; Disease; ENG gene; End Point; 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

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 TGFp 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 TGFp receptor signals in endothelial cells via a novel Smad-independent mechanism. Our studies demonstrate that endoglin is phosphorylated by ALK1 (Koleva et a/., in press), 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 TGFp 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, TGFp 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 TGFp 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（EC） 调节血管稳定性和体内平衡。我们的重点是了解 TGF β受体ALK 1及其共受体内皮糖蛋白。这些分子是重要的调节剂， 血管生成和伤口愈合，并且是血管疾病遗传性的靶基因 出血性毛细血管扩张症（HHT）。我们将检验内皮糖蛋白转导TGF β受体的假设， 通过一种新的Smad非依赖性机制在内皮细胞中的信号。我们的研究表明， 内皮糖蛋白被ALK 1磷酸化（Koleva等人，在出版），我们假设它调节内皮素的 对内皮细胞粘着斑重组、细胞骨架结构和迁移的影响。了解 这种新的内皮糖蛋白信号通路及其在脉管系统中的相关性，该提案的目的是： 具体目的1：检查TGF β受体介导的TGF β 1磷酸化的后果。 endoglin，以确定该途径如何调节EC功能。研究将侧重于以下方面的作用： 假定的蛋白质-蛋白质相互作用由内皮糖蛋白的胞质结构域介导，强调调节 EC粘着斑组装、微管发生、TGF β受体亚细胞定位和EC特异性 细胞间信号 具体目的2：检查内皮糖蛋白CD突变体在大肠杆菌中的EC靶向表达的后果。 卵黄囊脉管系统这一目标将强调细胞质结构域依赖的影响， 肾小管生成和血管生成重塑，并强调用于目标1的终点。结果 这些研究将阐明内皮糖蛋白调节内源性EC的机制 功能以及体内卵黄囊脉管系统内EC启动的细胞间信号。 特定目的3：表征在FVB：eng+/-小鼠模型中观察到的血管异常。 这一目标建立在新的初步数据的基础上，这些数据表明，表达在细胞膜上的杂合eng+/-表达， FVB小鼠遗传背景构成了HHT血管的潜在新型和有用的模型 畸形我们将研究FVB：eng+/-血管系统的结构和生化特性， 以了解其血管畸形的基础。该模型将用于测试是否 EC表达的转基因endoglin足以挽救血管缺陷。 我们提出的内皮联蛋白功能的小鼠转基因、遗传和生物化学模型将导致一个新的研究。 更深入地了解TGF β受体依赖性调节EC增殖的新机制， 粘附、小管形成和血管生成重塑，最终导致建立和维持 血管的完整性。拟议的研究与正常血管功能高度相关，并将阐明 endoglin在成人血管疾病中的作用