Novel Approaches in Treatment of Vascular Injury Following Balloon Angioplasty

治疗球囊血管成形术后血管损伤的新方法

• 批准号: 8209987
• 负责人: Yevgeniya Emre Koshman
• 金额: $ 5.39万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8209987
• 关键词: Accounting; Adaptor Signaling Protein; Address; Adenoviruses; Adult; Affect; American; Angioplasty; Arteries; Atherosclerosis; Balloon Angioplasty; Binding Sites; Blood Vessels; C-terminal; Carotid Arteries; Catalytic Domain; Cause of Death; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cell physiology; Cells; Data; Developed Countries; Development; Disease; Drug usage; Endothelium; Event; Extracellular Matrix; Family; Focal Adhesion Kinase 1; Focal Adhesions; Future; Gene Transfer; Goals; Growth Factor; Hyperplasia; Injury; Mediating; Modality; Modeling; Mutate; Myocardial Infarction; National Research Service Awards; PTK2 gene; Pathogenesis; Peripheral Vascular Diseases; Phosphotransferases; Play; Procedures; Protein Tyrosine Kinase; Rattus; Regulation; Research Project Grants; Role; Rupture; Series; Signal Transduction; Smooth Muscle Myocytes; Stents; Stroke; Structure; Techniques; Testing; Tissues; Tyrosine; Tyrosine Phosphorylation; United States; Up-Regulation; Vascular Diseases; Vascular remodeling; adenoviral-mediated; cell motility; disability; human BCAR1 protein; in vivo; inhibitor/antagonist; injured; knock-down; migration; mortality; novel strategies; overexpression; protein protein interaction; protein tyrosine kinase PYK2; public health relevance; research study; response; restenosis; vascular smooth muscle cell migration; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Atherosclerosis is the principal cause of myocardial infarction, stroke, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries. Percutaneous transluminal angioplasty has become a well-established technique for revascularization of occluded arteries. However, the long-term efficacy of the procedure remains limited by progressive vessel renarrowing (restenosis) within the following few months after angioplasty. Abnormal vascular smooth muscle cell (VSMC) proliferation and migration is thought to play an important role in the pathogenesis of both atherosclerosis and restenosis. The stimulation of VSMC proliferation and migration requires signals arising from both growth factors and the extracellular matrix (ECM). The focal adhesion kinase family of nonreceptor protein tyrosine kinases (PTKs) - focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (PYK2) - play a central role in modulating VSMC signal transduction. The overall goal of this research project is to develop novel approaches in treatment of vascular injury following balloon angioplasty. The overall hypothesis of my NRSA application is that upregulation of FRNK, a naturally occurring inhibitor of FAK and PYK2, during vascular remodeling reduces smooth muscle cell migration and proliferation, and this occurs via multiple mechanisms. In Specific Aim 1, I will examine the temporal relationship between FAK, PYK2 and endogenous FRNK expression following balloon angioplasty. In Specific Aim 2, I will use adenoviral-mediated gene transfer to overexpress and "knock down" FRNK following balloon injury of the rat carotid artery, and analyze their effects on VSMC migration and proliferation in the arterial wall as well as analyze FAK and PYK2-mediated signal transduction. In Specific Aim 3, I will examine the role of FRNK localization and FRNK tyrosine phosphorylation in the inhibition of FAK and/or PYK2- dependent signaling, and FRNK's independent signaling function as compared to cells depleted of FAK. I believe that the questions addressed by this project have fundamental importance to our understanding of VSMC signaling. Future therapies for vascular remodeling in arterial diseases may include regulation of VSMC FRNK expression to selectively limit VSMC migration and proliferation without inhibition of beneficial endothelial function. PUBLIC HEALTH RELEVANCE: Vascular diseases affect millions of Americans and are the leading cause of death and disability in the United States. I believe that the questions addressed by this project have fundamental importance to future therapies for vascular remodeling in arterial diseases such as atherosclerosis and restenosis.

描述（由申请人提供）：动脉粥样硬化是心肌梗死、中风和外周血管疾病的主要原因，占发达国家所有死亡率的近一半。经皮腔内血管成形术已成为一种成熟的闭塞动脉血运重建技术。然而，该手术的长期疗效仍然受到血管成形术后几个月内进行性血管再狭窄（再狭窄）的限制。血管平滑肌细胞（VSMC）的异常增殖和迁移被认为在动脉粥样硬化和再狭窄的发病机制中起重要作用。VSMC增殖和迁移的刺激需要来自生长因子和细胞外基质（ECM）的信号。粘着斑激酶家族的非受体蛋白酪氨酸激酶（PTKs）-粘着斑激酶（FAK）和富含脯氨酸的酪氨酸激酶-2（PYK 2）-在调节VSMC信号转导中起核心作用。本研究项目的总体目标是开发治疗球囊血管成形术后血管损伤的新方法。我的NRSA申请的总体假设是，在血管重塑过程中，FRNK（一种天然存在的FAK和PYK 2抑制剂）的上调减少了平滑肌细胞的迁移和增殖，这是通过多种机制发生的。在具体目标1中，我将研究球囊血管成形术后FAK，PYK 2和内源性FRNK表达之间的时间关系。在第二章中，我将利用腺病毒介导的基因转移，在大鼠颈动脉球囊损伤后过表达并“敲低”FRNK，分析其对动脉壁VSMC迁移和增殖的影响，并分析FAK和PYK 2介导的信号转导。在具体目标3中，我将研究FRNK定位和FRNK酪氨酸磷酸化在抑制FAK和/或PYK 2依赖性信号传导中的作用，以及与FAK耗尽的细胞相比FRNK的独立信号传导功能。我相信这个项目所解决的问题对我们理解VSMC信号具有根本的重要性。动脉疾病中血管重塑的未来疗法可能包括调节VSMC FRNK表达以选择性地限制VSMC迁移和增殖而不抑制有益的内皮功能。 公共卫生相关性：血管疾病影响数百万美国人，是美国死亡和残疾的主要原因。我相信，这个项目所解决的问题对动脉粥样硬化和再狭窄等动脉疾病的血管重塑的未来治疗具有根本的重要性。