Angiogenesis in Diseased Model

病变模型中的血管生成

基本信息

批准号：
7754860
负责人：
NILANJANA MAULIK
金额：
$ 35.02万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7754860
关键词：
3-nitrotyrosine Address Affect Age Agreement Angiogenic Factor Angiopoietin-1 Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibodies Antioxidants Apoptosis Area Arteries Atherosclerosis Attenuated Blood Glucose Blood Vessels Blood capillaries Blood flow Brain Hypoxia-Ischemia Caliber Cardiac Caveolae Caveolins Cell physiology Cells Centrifugation Clinical Collateral Circulation Comorbidity Complex Complications of Diabetes Mellitus Coronary Coronary Angiography Coronary Arteriosclerosis Coronary artery Data Deoxyguanosine Development Diabetes Mellitus Diabetic mouse Disease Dobutamine Down-Regulation Echocardiography Endothelial Cells Enzymes Equilibrium Etiology Event Exhibits Experimental Diabetes Mellitus Family suidae Funding Future Gene Expression Gene Targeting Genes Genetically Engineered Mouse Glucose Intolerance Glutathione Glutathione Disulfide Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Goals Grant Heart Heart failure Hour Human Hyperglycemia Hypoxia Hypoxia Inducible Factor Imaging technology Immunoblotting In Vitro Individual Infarction Injection of therapeutic agent Isoprostanes Laboratories Malondialdehyde Manganese Superoxide Dismutase Measures Mediating Mediator of activation protein Membrane Membrane Microdomains Membrane Proteins Messenger RNA Modeling Molecular Molecular Biology Monitor Motivation Mus Muscle Cells Myocardial Myocardial Infarction Myocardial Ischemia Myocardium NG-Nitroarginine Methyl Ester Nitric Oxide Nitric Oxide Synthase Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Patients Phosphorylation Physiological Physiology Platelet Factor 4 Play Principal Investigator Production Property Proteins Proto-Oncogene Proteins c-akt Rattus Reactive Oxygen Species Regulation Reporting Research Resveratrol Risk Role Series Signal Transduction Signaling Molecule Solutions Staging Streptozocin Stress Stress Tests Sucrose Sulfhydryl Compounds System Techniques Testing Therapeutic Thioredoxin Time Tissues Transcriptional Regulation Transgenic Animals Transgenic Organisms Translating Tromethamine Tumor Angiogenesis United States Up-Regulation Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Ventricular Function Wild Type Mouse Work X-Ray Computed Tomography angiogenesis beta catenin capillary caveolin 1 caveolin-3 clinically significant combination gene therapy density design diabetic diabetic patient diabetic rat gene therapy heme oxygenase-1 human NOS3 protein hypoxia inducible factor 1 improved in vivo in vivo Model inhibitor/antagonist interdisciplinary approach interest mouse model neovascular neovascularization non-diabetic novel therapeutics overexpression programs protein expression protein function protein protein interaction receptor red wine research study response tool treatment strategy vasculogenesis

项目摘要

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.

描述（由申请人提供）：糖尿病是心力衰竭（HF）患者最重要的合并症，它对心力衰竭和缺血性心脏病患者的预后产生不利影响。其特征是响应冠状动脉缺血事件的侧支血管形成减少。因此，在患糖尿病的 26 周内，毛细血管密度和直径逐渐下降超过 20%。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，在发育性血管形成中发挥关键作用，被发现在糖尿病并发症中受到抑制。在临床和实验性糖尿病中已有冠状动脉侧支循环异常的报道。我们研究缺血再灌注心脏氧化还原信号的最初和持续动机引导我们进入糖尿病氧化还原调节和应激信号的新研究领域。我们的实验室最近证明硫氧还蛋白 (Trx) 是一种氧化还原活性蛋白，可诱导 HO-1 和 VEGF，从而保护心肌免受氧化应激。 Trx 具有血管生成潜力，可能有助于缺血/梗塞心肌中血管发生或血管生成，从而促进血管的从头发育。我们该项目的长期目标是了解氧化应激引起的糖尿病心力衰竭（HF）异常，并制定有效的治疗策略来治疗未来的糖尿病患者。因此，本研究将尝试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一个重要的临床问题。这项研究将采用广泛的多学科方法，结合各种技术、现代分子生物学、成像技术、基因治疗、基因靶向和生理学。目标 I. 将研究氧化应激/氧化还原状态对糖尿病病情加重的影响以及 Caveolin、Trx、HO-1 和 VEGF 表达和血管生成。目标二。 Thiredoxin-1 的过度表达涉及 HO-1、VEGF/VEGFR2 和 eNOS 表达增加，随后新血管形成增加。目标三。将探讨糖尿病动物中 GSK-3 β 和 β-连环蛋白介导的 VEGF 信号传导与血管生成的关系。目标四。 Ad-VEGF 和 Ad-Ang-1 的联合基因治疗触发生存信号和新血管形成。将使用链脲佐菌素诱导的糖尿病大鼠和基因工程小鼠模型精心设计的一系列实验。总的来说，这项研究将有助于我们理解与糖尿病相关疾病相关的血管生成调节机制，并可能提供治疗缺血性疾病的新治疗策略。