Angiogenic Regulators in Ischemic Disorders

缺血性疾病中的血管生成调节剂

• 批准号: 9108386
• 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
• 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/9108386
• 关键词: Address; Affect; Angiogenesis Inhibition; Animal Model; Area; Arteriosclerosis; Attention; Biomedical Research; Blood Circulation; Blood capillaries; Blood flow; Breeding; Cardiovascular Diseases; Cell Death; Cell Survival; Cells; Clinic; Clinical; Controlled Environment; Coronary; Data; Disease; Down-Regulation; Echocardiography; Endothelial Cells; Environment; Equilibrium; Feedback; Figs - dietary; Fluorescein-5-isothiocyanate; Gene Expression; Genetic Engineering; Genetic Models; Genetic Techniques; Goals; Growth; Health; Heart Diseases; Heart failure; Hindlimb; Image; Impairment; Inflammation; Infusion procedures; Injury; Ischemia; Knowledge; Lectin; Left ventricular structure; Light; Limb structure; Malignant Neoplasms; Measures; Mediating; Medical; Microspheres; Modeling; 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; in vivo; interdisciplinary approach; multicatalytic endopeptidase complex; neovascularization; new therapeutic target; novel; prevent; repaired; small molecule; success; therapeutic angiogenesis; tumor growth; ubiquitin-protein ligase

 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）：生理学和病理学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（抑制血管形成和血流量）可以治疗视网膜病和恶性肿瘤生长。尽管心力衰竭和严重肢体缺血模型的临床医学、介入和外科治疗取得了重大进展，但解决这些疾病及其治疗的正确答案仍然难以捉摸。治疗性血管生成可能是迄今为止治疗缺血性疾病的唯一方法，但取得的成功有限。我们提出的目标将有助于阐明抗原途径的潜在分子机制，通过使用缺血挑战的临床前模型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转基因动物，并利用它们在缺血器官/组织中执行挽救受损血管生成技术。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) 激活血管生成过程中的调节作用。我们发现Peli1通过调节和抑制硫氧还蛋白相互作用蛋白（TXNIP）而成为后肢新生血管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。因此，我们的总体假设是，由于 Peli1-Trx1-VEGF 信号传导的破坏和缺血组织中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： 具体目标 I - 在缺血性挑战模型（HLI、MI）中检查 Peli1 介导的新血管形成。具体目标 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。基因工程 Peli1 和 Flk-1 小鼠将用于评估我们提出的与缺血性损伤模型中血管生成相关的假设。这项研究将利用各种现代技术和强大的动物模型采用多学科方法。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，Trx1 控制氧化还原状态转变为过度还原或氧化环境，这种环境通常会破坏与血管生成信号相关的各种调节剂（HO-1、VEGF）。我们相信 Peli1 是小分子治疗的潜在候选者，用于治疗与血管生成相关的缺血性疾病。