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: 7586701
• 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
• 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/7586701
• 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

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.

本实验室的长期目标是了解内皮细胞（ECs）调节血管稳定性和体内平衡的过程。我们的重点是了解tgf - β受体ALK1与其协同受体内啡肽之间的功能关系。这些分子是血管生成和伤口愈合的重要调节因子，也是血管疾病遗传性出血性毛细血管扩张症（HHT）的靶基因。我们将测试内啡肽通过一种新的smad独立机制在内皮细胞中传导tgf - β受体信号的假设。我们的研究表明，内啡肽被ALK1磷酸化，我们假设它调节内啡肽？对上皮细胞黏附重组、细胞骨架结构和迁移的影响。为了了解这种新的内啡肽信号通路及其在血管系统中的相关性，本提案的目的是：具体目的1：检查tgf - β受体介导的内啡肽磷酸化的后果，以确定该途径如何调节EC功能。研究将集中在内啡肽介导的蛋白质-蛋白质相互作用的作用上。在细胞质结构域，强调EC局灶黏附组装、小管形成、tgf - β受体亚细胞定位和EC特异性细胞间信号的调节。特异性目的2：研究蛋黄囊血管中内啡肽CD突变体ec靶向表达的后果。该目的将强调细胞质结构域依赖性对EC小管形成和血管新生重塑的影响，并强调目的1的终点。这些研究结果将阐明内啡肽的作用机制。在体内卵黄囊血管系统内，卵黄囊内在功能以及卵黄囊内卵黄囊启动的细胞间信号的调控。