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（由适用提供）：生理和病理血管生成表示当今生物医学研究最热门的领域之一。治疗性血管生成（血管密度和血流的增加）可以修复心肌梗塞，肢体缺血和动脉硬化，而抑制病理血管生成（抑制血管形成和血液流动）可以治疗视网膜病变和恶性肿瘤生长。在诊所的心力衰竭和关键的肢体缺血模型中，在医疗，介入和手术疗法方面取得了重大进展，仍然是解决这些疾病的适当答案，其治疗仍然难以捉摸。治疗性血管生成可能是迄今为止缺血性疾病的唯一可用治疗方法，其成功率有限。我们提出的目标将有助于阐明抗原途径的潜在分子机制，通过使用局部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产生新型的转基因动物，并使用它们在缺血性器官/组织中进行救援受损的血管生成技术。在这里，我们将研究E3连接酶Pellino-1（Peli1）中VEGF的先前未知功能，介导的硫氧还蛋白-1（TRX1）在血管生成激活中的调节。我们发现，PELI1通过控制和抑制硫氧还蛋白相互作用蛋白（TXNIP），是后肢和心肌缺血中新血管形成的临界阳性调节剂。该项目的长期目标是使用后肢缺血模型（HLI）和心肌梗死（MI）了解和探索外周手术（PAD）中血管生成受损的原因。因此，我们的总体假设是，缺血导致血管生成异常或受损，并且由于PELI1-TRX1-TRX1-VEGF信号的破坏以及缺血性组织中氧化还原等效的丧失，导致血管生成和确定的血液灌注。我们提出了三个具体目标：特定目的I-在缺口挑战模型（HLI，MI）中检查PELI1介导的新血管化。特定的目标II-阐明了各种脱落模型中PELI1介导的氧化还原信号传导的下游分子机制。特定的目标是使用遗传模型检查和评估PELI1的临床和功能意义。基因工程性的PELI1和FLK-1小鼠将用于评估我们在所提出的缺血性损伤模型中与血管生成有关的假设。这项研究将使用各种现代技术和强大的动物模型来调整多学科方法。总的来说，拟议的研究将有助于我们对PELI1介导的TRX1激活的分子机制的理解，TRX1控制了从转移到过度降低或氧化物环境的氧化还原状态，通常会破坏与血管源性信号相关的各种调节剂（HO-1，VEGF）。我们认为，PELI1是小分子治疗的潜在候选者，以控制与血管生成相关的缺血性疾病。