Role of Tie-1 in Vascular Inflammation and Atherosclerosis

Tie-1 在血管炎症和动脉粥样硬化中的作用

• 批准号: 7774291
• 负责人: Barden Chunkong Chan
• 金额: $ 12.66万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774291
• 关键词: Abdomen; Accounting; Affect; Aneurysm; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Blood flow; CXCL10 gene; Cell physiology; Collagen; Country; Data; Development; Diagnostic; Disease; E-Selectin; End stage renal failure; Endothelial Cells; Endothelium; Environment; Event; Fibronectins; Functional disorder; Gel; Goals; Grant; Health; Hereditary Disease; Hypertension; Implant; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Interleukin-6; Kidney; Kidney Diseases; Knockout Mice; Light; Location; MAPK14 gene; Messenger RNA; Mission; Modeling; Molecular; Mono-S; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Pathway interactions; Perfusion; Phenotype; Play; Prevention; Principal Investigator; Property; Proteins; Proteomics; Renal Artery Stenosis; Renal function; Research; Risk Factors; Role; Signal Pathway; Site; Smooth Muscle Myocytes; Testing; Therapeutic; Transgenic Mice; Trees; Tyrosine; Vascular Cell Adhesion Molecule-1; Veins; Western World; aortic valve; atherogenesis; cell motility; cell type; design; hemodynamics; implantation; improved; in vitro activity; in vivo; inflammatory marker; migration; mitogen-activated protein kinase p38; monocyte; mouse model; overexpression; preference; programs; promoter; receptor; reconstruction; renal artery; research study; response; vascular inflammation; Abdomen; Accounting; Affect; Aneurysm; Aorta; Apolipoprotein E; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood Vessels; Blood flow; CXCL10 gene; Cell physiology; Collagen; Country; Data; Development; Diagnostic; Disease; E-Selectin; End stage renal failure; Endothelial Cells; Endothelium; Environment; Event; Fibronectins; Functional disorder; Gel; Goals; Grant; Health; Hereditary Disease; Hypertension; Implant; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Intercellular adhesion molecule 1; Interleukin-6; Kidney; Kidney Diseases; Knockout Mice; Light; Location; MAPK14 gene; Messenger RNA; Mission; Modeling; Molecular; Mono-S; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Pathway interactions; Perfusion; Phenotype; Play; Prevention; Principal Investigator; Property; Proteins; Proteomics; Renal Artery Stenosis; Renal function; Research; Risk Factors; Role; Signal Pathway; Site; Smooth Muscle Myocytes; Testing; Therapeutic; Transgenic Mice; Trees; Tyrosine; Vascular Cell Adhesion Molecule-1; Veins; Western World; aortic valve; atherogenesis; cell motility; cell type; design; hemodynamics; implantation; improved; in vitro activity; in vivo; inflammatory marker; migration; mitogen-activated protein kinase p38; monocyte; mouse model; overexpression; preference; programs; promoter; receptor; reconstruction; renal artery; research study; response; vascular inflammation

DESCRIPTION (provided by applicant): The long-term goal of this study is to examine the role of Tie-1 in vascular inflammation and atherosclerosis. Tie-1 is upregulated at atherosclerosis-prone arterial branch points and in atherosclerotic lesions. We postulate that Tie-1 activation at these sites is one of the precipitating molecular events that initiates the development of atherosclerosis. Indeed, we have evidence to show that Tie-1 activity in vitro induces endothelial inflammation. The experiments proposed in this grant are designed to probe the connection between Tie-1 and atherosclerosis and to gain mechanistic understanding of the disease at the molecular level. Specifically, we propose: 1) To study the proinflammatory property of Tie-1 in endothelial cells in vitro by examining the roles of ICAM-1, VCAM-1, E-selectin, IL-6, and IP-10 using both mono-cell-type culture experiments and an artificial arterial wall reconstruction model; 2) To dissect signaling pathways responsible for Tie-1-induced inflammatory response by elucidating the mechanism of activation of p38 MAP kinase and by identifying tyrosine-phosphorylated proteins via functional proteomics and ; 3) To study the role of Tie-1 in inflammation and atherosclerosis development in vivo by using a collagen-fibronectin gel implantation mouse model and a transgenic mouse line that conditionally expresses Tie-1 in an endothelial specific manner. Results from these experiments may shed light on the question why atherosclerotic lesions tend to develop at particular vascular sites. This proposal is highly relevant to the mission of NIDDK, because atherosclerosis affects kidney function. Atherosclerosis is the main cause of renal artery stenosis (RAS), accounting for 90% of the cases. RAS causes narrowing of the renal artery and reduction in renal perfusion, resulting in hypertension. Ultimately, ischemic nephropathy can occur, leading to end stage renal failure. Atherosclerotic plaques in RAS usually develop at the ostium of the renal artery. Strikingly, Tie-1 is dramatically upregulated at the aorta-renal artery junction. Therefore, understanding the role of Tie-1 in atherosclerosis may have a direct impact on the prevention of RAS. Atherosclerosis is one of the major health problems in western countries. An improved mechanistic understanding of vascular inflammation leading to atherosclerosis will yield invaluable information necessary for diagnostic and/or therapeutic purposes.

描述（由申请人提供）： 这项研究的长期目标是检查TIE-1在血管炎症和动脉粥样硬化中的作用。在容易发生动脉粥样硬化的动脉分支点和动脉粥样硬化病变中，TIE-1上调。我们假设这些位点的TIE-1激活是引发动脉粥样硬化发展的沉淀分子事件之一。确实，我们有证据表明，TIE-1活性在体外会诱导内皮炎症。该赠款中提出的实验旨在探测TIE-1与动脉粥样硬化之间的联系，并在分子水平上对疾病的机械理解。具体而言，我们提出：1）使用单声道细胞型培养实验和人造动脉壁再现模型，通过检查ICAM-1，VCAM-1，E-S-Electin，IL-6和IP-10的作用来研究体外内皮细胞中TIE-1的促炎特性； 2）通过阐明p38 MAP激酶的激活机制，并通过功能蛋白质组学鉴定p38 MAP激酶的激活机理，并通过阐明p38 MAP激酶的激活机理，并通过识别p38 MAP激酶的激活机制来解剖信号传导途径； 3）研究TIE-1通过使用胶原蛋白 - 纤维蛋白凝胶植入小鼠模型和以内皮特异性表达TIE-1的转基因小鼠系在体内炎症和动脉粥样硬化发展的作用。这些实验的结果可能会阐明为什么动脉粥样硬化病变倾向于在特定的血管部位发展。该建议与NIDDK的任务高度相关，因为动脉粥样硬化会影响肾脏功能。动脉粥样硬化是肾动脉狭窄（RAS）的主要原因，占病例的90％。 RA会导致肾动脉的狭窄和肾脏灌注的减少，导致高血压。最终，可能发生缺血性肾病，导致末期肾衰竭。 RAS中的动脉粥样硬化斑块通常在肾动脉的口腔上发展。令人惊讶的是，在主动脉 - 肾脏交界处，TIE-1急剧上调。因此，了解TIE-1在动脉粥样硬化中的作用可能会直接影响预防RAS。 动脉粥样硬化是西方国家的主要健康问题之一。对导致动脉粥样硬化的血管炎症的改进的机械理解将产生诊断和/或治疗目的所需的宝贵信息。