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: 8402612
• 负责人: Yevgeniya Emre Koshman
• 金额: $ 2.38万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402612
• 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.

描述（由申请人提供）：动脉粥样硬化是心肌梗塞，中风和周围血管疾病的主要原因，占发达国家所有死亡率的一半。经皮易流血管成形术已成为闭塞动脉血运重建的完善技术。然而，在血管成形术后的接下来的几个月内，该过程的长期疗效仍受到进行性血管重生（再狭窄）的限制。异常的血管平滑肌细胞（VSMC）增殖和迁移被认为在动脉粥样硬化和再狭窄的发病机理中起重要作用。 VSMC增殖和迁移的刺激需要由生长因子和细胞外基质（ECM）引起的信号。非受体蛋白酪氨酸激酶（PTK）的局灶性激酶家族 - 局灶性粘附激酶（FAK）和富含脯氨酸的富含酪氨​​酸激酶-2（PYK2） - 在调节VSMC信号转导的调节中起着核心作用。该研究项目的总体目的是开发在气球血管成形术后血管损伤治疗的新方法。我的NRSA应用的总体假设是，在血管重塑期间，FRNK（一种天然存在的FAK和PYK2抑制剂）上调会减少平滑肌细胞的迁移和增殖，这通过多种机制发生。在特定的目标1中，我将检查球囊血管成形术后FAK，PYK2和内源性FRNK表达之间的时间关系。在特定的目标2中，我将使用腺病毒介导的基因转移到过表达并“击倒”大鼠颈动脉损伤后“击倒” FRNK，并分析它们对动脉壁中VSMC迁移和增殖的影响，并分析FAK和PYK2和PYK2介导的信号转移。在特定目标3中，我将研究FRNK定位和FRNK酪氨酸磷酸化在抑制FAK和/或PYK2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。我认为，该项目解决的问题对于我们对VSMC信号的理解至关重要。对动脉疾病的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，而不会抑制有益的内皮功能。