Angiogenic Regulators in Ischemic Disorders

 描述(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中最热门的领域之一。治疗性血管生成(增加血管密度和血流量)可以修复心肌梗死、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)则可以治疗视网膜病变和恶性肿瘤生长。尽管心力衰竭和严重肢体缺血模型的临床治疗在医学、介入和外科治疗方面取得了重大进展，但解决这些疾病的适当答案及其治疗仍然难以捉摸。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，但成效有限。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的转基因动物，并使用它们在缺血器官/组织中执行修复受损的血管生成技术。在这里，我们将研究先前未知的在E3连接酶Pellino-1(PELI1)介导的硫氧还蛋白-1(Trx1)调节血管生成激活中的作用。我们发现，Peli1通过调节和抑制硫氧还蛋白相互作用蛋白(TXNIP)，对后肢新生血管和心肌缺血起着关键的正向调节作用。我们这个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)血管生成障碍的原因。因此，我们的总体假设是，缺血导致血管生成异常或受损，血液灌注量恶化，这是由于缺血组织中Peli1-Trx1-VEGF信号的中断和氧化还原平衡的丧失。我们提出了三个特定目标：特定目标I--研究PEL1介导的缺血模型(HLI，MI)中的新生血管形成。特定目的II-阐明Peli1介导的氧化还原信号在各种疾病模型中的下游分子机制。具体目的III-使用遗传模型检查和评估PELI1的临床和功能意义。基因工程的Peli1和Flk-1小鼠将被用来评估我们的假说与所提出的缺血损伤模型中血管生成的关系。这项研究将采用多学科方法，使用各种现代技术和强大的动物模型。总之，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控制氧化还原状态向过度还原或氧化环境转变，而过度还原或氧化环境通常会扰乱与血管生成信号相关的各种调节剂(HO-1，VEGF)。我们相信，Peli1是一种潜在的小分子治疗方法，可用于治疗与血管生成相关的缺血性疾病。

 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.