Angiogenic Regulators in Ischemic Disorders

缺血性疾病中的血管生成调节剂

基本信息

批准号：
9245714
负责人：
NILANJANA MAULIK
金额：
$ 39.99万
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：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9245714
关键词：
Address Affect Alpha Cell Angiogenesis Inhibition Animal Model Area Arteriosclerosis Attention Biomedical Research Blood Circulation Blood capillaries Blood flow Cardiovascular Diseases Cell Death Cell Survival Cells Clinic Clinical Coronary Crossbreeding Data Disease Disease model Down-Regulation Echocardiography Endothelial Cells Environment Equilibrium Feedback Fluorescein-5-isothiocyanate Gene Expression Genetic Engineering Genetic Models Genetic Techniques Goals Growth Growth Factor Heart Diseases Heart failure Hindlimb Image Impairment Inflammation Infusion procedures Injury Intervention Ischemia Knowledge Lectin Left ventricular structure Light Limb structure Malignant Neoplasms Measures Mediating Medical Microspheres Modeling Modernization Molecular Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardial perfusion Operative Surgical Procedures Organ Oxidation-Reduction Pathologic Neovascularization Pathway interactions Perfusion Peripheral Peripheral arterial disease Physiological Play Postoperative Period Pre-Clinical Model Process Proteins Receptor Signaling Regulation Retinal Diseases Role Scheme Severities Signal Transduction Signaling Molecule Skin Stress Surgical Flaps System TXN gene TXNIP gene Techniques Testing Tissues Toll-like receptors Transgenic Animals Ubiquitin Ubiquitination United States Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascular blood supply Wild Type Mouse Wound Healing angiogenesis base blood perfusion capillary cell type density design gene therapy heart function immunoregulation in vivo interdisciplinary approach multicatalytic endopeptidase complex neovascularization new therapeutic target novel prevent public health relevance repaired small molecule success therapeutic angiogenesis tumor growth ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Physiological as well as pathological angiogenesis denotes one of the hottest areas of biomedical research today. Therapeutic angiogenesis (increase in vessel density and blood flow) can repair myocardial infarction, limb ischemia and arteriosclerosis whereas inhibition of pathological angiogenesis (inhibition of vessel formation and blood flow) can treat retinopathies and malignant tumor growth. Inspite significant progress in medical, interventional and surgical therapy in the clinics for heart failure and critical limb ischemia models, still the proper answer to addressing these illnesses and their treatment still remains elusive. Therapeutic angiogenesis, which is probably the only treatment available so far for ischemic diseases, has had limited success. Our proposed aims will help elucidate the underlying molecular mechanism of antigenic pathway, reveal new antigenic modulators by using ischemically challenged, pre-clinical models. We will use state-of- the-art genetic techniques to generate novel transgenic animals and use them to perform a rescue-impaired angiogenesis technique in ischemic organs/tissues. Here we are going to examine a previously unknown function of VEGF in an E3 ligase Pellino-1 (Peli1) mediated regulation of Thioredoxin-1 (Trx1) in the activation of angiogenesis. We found that Peli1 serve as a critical positive regulator of neovascularization in Hind limb and myocardial ischemia by regulating and inhibiting thioredoxin interacting protein (TXNIP). Our long-term goal of this project is to understand and explore the cause of impairment of angiogenesis in peripheral arterial disease (PAD) using hind limb ischemia model (HLI) and myocardial infarction (MI). Therefore, our overall hypothesis is that ischemia leads to abnormal or impaired angiogenesis and deteriorated blood perfusion due to the disruption of Peli1-Trx1-VEGF signaling and loss of redox equilibrium in the ischemic tissue. We proposed three specific aims: Specific Aim I- To examine Peli1 mediated neovascularization in ischemically challenged models (HLI, MI). Specific Aim II - To elucidate a downstream molecular mechanism of Peli1- mediated redox signaling in various diseased models. Specific Aim III- To examine and assess the clinical and functional significance of Peli1 using genetic models. Genetically engineered Peli1 and Flk-1 mice will be used to evaluate our hypothesis in relation to angiogenesis in models of ischemic injury as proposed. This study will adapt multidisciplinary approaches using various modern techniques and powerful animal models. Collectively, the proposed study will contribute to our understanding of the molecular mechanism of Peli1 mediated activation of Trx1, which controls the redox state from shifting to an overly reductive or an oxidative environment that generally disrupts various modulators (HO-1, VEGF) related to angiogenic signaling. We believe that Peli1 is a potential candidate for small molecule treatment to manage ischemic disorders associated with angiogenesis.

描述（由申请人提供）：生理性和病理性血管生成是当今生物医学研究最热门的领域之一。治疗性血管生成（增加血管密度和血流量）可以修复心肌梗塞、肢体缺血和动脉硬化，而抑制病理性血管生成（尽管在医学上取得了重大进展，但抑制血管形成和血流仍可以治疗视网膜病和恶性肿瘤生长。临床上针对心力衰竭和严重肢体缺血模型的介入和手术治疗仍然是解决这些疾病的正确答案，并且其治疗方法仍然难以捉摸。治疗性血管生成可能是迄今为止唯一可用的缺血性疾病治疗方法。我们提出的目标将有助于阐明抗原途径的潜在分子机制，通过使用缺血性挑战的临床前模型来揭示新的抗原调节剂。我们将使用最先进的遗传技术来生成。新型转基因动物，并使用它们在缺血器官/组织中执行挽救受损的血管生成技术在这里，我们将检查 VEGF 在 E3 连接酶 Pellino-1 (Peli1) 介导的硫氧还蛋白-1 (Trx1) 调节中的功能。）我们发现 Peli1 通过调节和抑制后肢新血管形成和心肌缺血的关键正调节因子。我们该项目的长期目标是利用后肢缺血模型（HLI）和心肌梗死（MI）来了解和探索外周动脉疾病（PAD）中血管生成受损的原因。我们的总体假设是，由于 Peli1-Trx1-VEGF 信号传导的破坏和细胞内氧化还原平衡的丧失，缺血会导致血管生成异常或受损以及血液灌注恶化。我们提出了三个具体目标：特定目标 I - 在缺血性挑战模型（HLI、MI）中检查 Peli1 介导的新生血管形成。特定目标 II - 阐明各种疾病模型中 Peli1 介导的氧化还原信号传导的下游分子机制。具体目标 III - 使用遗传模型检查和评估 Peli1 的临床和功能意义，将使用基因工程 Peli1 和 Flk-1 小鼠来评估我们与血管生成相关的假设。总的来说，这项研究将有助于我们理解 Peli1 介导的 Trx1 激活的分子机制，该机制控制着氧化还原状态。转向过度还原或氧化环境，通常会破坏与血管生成信号传导相关的各种调节剂（HO-1、VEGF），我们相信 Peli1 是小分子治疗的潜在候选者。与血管生成相关的缺血性疾病。