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：
7262739
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/7262739
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

项目摘要

DESCRIPTION (provided by applicant): 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¿ 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¿ 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 TGF¿ 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¿ 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¿ 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.

描述（由申请人证明）：理解内皮细胞（ECS）ESSEL稳定性和稳态的过程的长期目标。受体ALK1及其共受体，这些分子是血管生成和伤口愈合的重要调节剂，遗传性疾病遗传性出血性毛细血管炎（HHT）。通过新型的SMAD侵入机制在其他细胞中的受体信号Andoglin信号通路，在Vascularture中相关，目的是1：检查TGF¿受体介导的磷酸化确定了该途径的经常性相互作用。受体亚细胞定位和EC特异性的细胞间信号。在fvb中观察到的蛋黄囊血管中的IC液体间信号的功能是：英语以新的初步数据为基础血管畸形。 tgf¿对EC的增长，粘附，微管发生和血管生成的重塑。