Angiogenesis in Diseased Model

描述（由申请方提供）：糖尿病是心力衰竭（HF）患者最重要的合并症，对HF和缺血性心脏病患者的结局产生不良影响。其特征在于响应于冠状动脉缺血事件的侧支血管形成减少。因此，毛细血管密度和直径在糖尿病26周内表现出超过20%的进行性降低。血管内皮生长因子（VEGF）是生理和病理条件下新生血管形成的主要介质，在发育血管形成中起关键作用，在糖尿病并发症中被发现受到抑制。糖尿病患者冠状动脉侧支循环障碍在临床和实验中都有报道。我们对缺血再灌注心脏中氧化还原信号的最初和持续的研究动机使我们进入了糖尿病氧化还原调节和应激信号的新研究领域。硫氧还蛋白（Thioredoxin，Trx）是一种具有氧化还原活性的蛋白质，可诱导HO-1和VEGF的表达，从而保护心肌免受氧化应激。Trx具有血管生成潜力，可能通过缺血/梗死心肌中的血管生成或血管生成促进血管的新生。本项目的长期目标是了解氧化应激诱导的糖尿病心力衰竭（HF）异常，并建立有效的治疗策略，以治疗糖尿病患者的未来。因此，本研究将试图通过鉴定糖尿病动物中Trx-VEGF信号传导的潜在候选者来解决重要的临床问题。本研究将采用广泛的多学科方法，结合联合收割机各种技术，现代分子生物学，成像技术，基因治疗，基因靶向和生理学。艾姆岛将沿着小窝蛋白、Trx、HO-1和VEGF表达和血管生成研究氧化应激/氧化还原状态对糖尿病状况增加的影响。Aim II. Thiredoxin-1的过表达涉及HO-1、VEGF/VEGFR 2和eNOS表达的增加，随后是新血管形成的增加。Aim III.将探索糖尿病动物中GSK-3 β和β-连环蛋白介导的VEGF信号传导与血管生成的相关性。目标四。Ad-VEGF和Ad-Ang- 1的联合基因治疗触发存活信号和新血管形成。本研究采用链脲佐菌素诱导的糖尿病大鼠模型和基因工程小鼠模型进行了一系列实验。总的来说，这项研究将有助于我们了解与糖尿病相关疾病相关的血管生成调节机制，并可能提供新的治疗缺血性疾病的治疗策略。

DESCRIPTION (provided by applicant): Diabetes is the most significant co-morbidity of patients with heart failure (HF), which adversely affects outcomes in patients with HF and ischemic heart disease. It is characterized by a decreased collateral vessel formation in response to coronary ischemic events. Therefore capillary density and diameter exhibited progressive decreases of more than 20% over 26 week of diabetes. Vascular endothelial growth factor (VEGF) is a major mediator of neovascularization in physiological and pathological conditions with crucial roles in developmental blood vessel formation was found to be inhibited in diabetic complications. Abnormalities of the coronary collateral circulation have been reported in clinical and experimental diabetes mellitus. Our initial and continuing motivation to study of REDOX SIGNALING IN ISCHEMIC REPERFUSED heart leads us to step into a new research field of redox regulation and stress signal in diabetes mellitus. Thioredoxin (Trx) a redox active protein has recently been shown by our laboratory to induce HO-1 and VEGF that protects myocardium from oxidative stress. Trx has angiogenic potential, which may contribute to de novo development of vessels by vasculogenesis or angiogenesis in ischemic/infarcted myocardium. Our long-term goal of this project is to understand the oxidative stress induced abnormalities in diabetic heart failure (HF) and to establish effective therapeutic strategies to treat diabetic patients in future. Thus, this study will attempt to address an important clinical issue by identifying potential candidates of Trx-VEGF signaling in diabetic animals. This study will utilize a broad multidisciplinary approach that will combine various techniques, modern molecular biology, imaging technology, gene therapy, gene targeting and physiology. Aim I. The impact of oxidative stress/redox status with increased diabetic condition will be studied along with caveolin, Trx, HO-1 and VEGF expression and angiogenesis. Aim II. Overexpression of Thiredoxin-1 involves increased HO-1, VEGF/VEGFR2 and eNOS expression followed by increased neovascularization. Aim III. Involvement of GSK-3 beta and beta-catenin mediated VEGF signaling in diabetic animals will be explored related to angiogenesis. Aim IV. Combination gene therapy with Ad-VEGF and Ad-Ang- 1 triggers survival signal and neovascularization. Thoughtfully designed series of experiments in streptozotocin-induced diabetic rat and genetically engineered mouse model will be used. Collectively, the proposed study will contribute to our understanding of the mechanisms that regulate angiogenesis in association with diabetic-related disorders, and may provide novel therapeutic treatment strategies to cure ischemic disease.