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）的过程 调节船舶稳定性和体内平衡。我们的重点是了解 TGFP受体ALK1及其共受体内Oglin。这些分子是 血管生成和伤口愈合，是血管疾病遗传性的靶基因 出血性毛细血管扩张（HHT）。我们将测试内源传递TGFP受体的假设 内皮细胞中的信号通过新型的SMAD独立机制。我们的研究表明 Endoglin被ALK1（印刷中的Koleva et a/。）磷酸化，我们假设调节内og EC中对局灶性粘附重组，细胞骨架结构和迁移的影响。理解 这个新颖的内聚糖信号通路及其在脉管系统中的相关性，该提议的目的是： 特定目标1：检查TGFP受体介导的磷酸化的后果 内og以确定该途径如何调节EC功能。研究将侧重于 推定的蛋白质 - 蛋白质相互作用由内og的胞质结构域介导，强调调节 EC焦点粘附组件，微管生成，TGFP受体亚细胞定位和EC特异性 细胞间信号。 特定目的2：检查内og的EC靶向表达在中的后果 蛋黄囊脉管系统。这个目标将强调胞质域对EC的影响 微管发生和血管生成重塑，并强调用于目标1的终点。结果 在这些研究中获得的将阐明内源于内在EC的基本机制 在体内蛋黄囊脉管系统内的功能以及EC发起的细胞间信号。 特定目标3：表征FVB中观察到的血管异常：ENG +/-小鼠模型。 此目标以新的初步数据为基础，这表明杂合ENG +/-在 FVB小鼠遗传背景构成了HHT血管的潜在新颖且有用的模型 畸形。我们将研究FVB的结构和生化特性：ENG +/-脉管系统 为了了解其血管畸形的基础。然后将使用该模型测试是否 EC表达的转基因内og足以挽救血管缺陷。 我们提出的小鼠转基因，遗传和生化模型的内源功能将导致 对TGFP受体依赖性调节EC增殖的新机制的更深入了解， 在建立和维持中达到顶点的粘附，微管发生和血管生成重塑 船只完整性。拟议的研究与正常血管功能高度相关，并将阐明 内聚会在成人发作的血管疾病中的作用。