Angiogenic Regulators in Ischemic Disorders

 描述（由申请人提供）：生理和病理性血管生成是当今生物医学研究的最热门领域之一。治疗性血管生成（增加血管密度和血流）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）可以治疗视网膜病和恶性肿瘤生长。尽管在心力衰竭和严重肢体缺血模型的临床中，医疗、介入和手术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，这可能是唯一可用的治疗缺血性疾病迄今为止，取得了有限的成功。本研究的目的是通过缺血性脑损伤的临床前模型，阐明抗原通路的分子机制，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/组织中进行拯救受损血管生成技术。在这里，我们将研究VEGF在E3连接酶Pellino-1（Peli 1）介导的硫氧还蛋白-1（Trx 1）在血管生成激活中的调节中的一个先前未知的功能。我们发现Peli 1通过调节和抑制硫氧还蛋白相互作用蛋白（TXNIP），在后肢血管新生和心肌缺血中起重要的正性调节作用。本课题的长期目标是利用后肢缺血模型（HLI）和心肌梗死模型（MI）来了解和探讨外周动脉疾病（PAD）血管生成障碍的原因。因此，我们的总体假设是，缺血导致异常或受损的血管生成和恶化的血液灌注，由于Peli 1-Trx 1-VEGF信号传导的中断和缺血组织中氧化还原平衡的丧失。我们提出了三个具体的目标：具体目标I-检查Peli 1介导的缺血激发模型（HLI，MI）中的新血管形成。具体目的II -阐明Peli 1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Peli 1的临床和功能意义。基因工程Peli 1和Flk-1小鼠将被用来评估我们的假设在缺血性损伤模型中的血管生成的建议。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。总的来说，拟议的研究将有助于我们理解Peli 1介导的Trx 1激活的分子机制，该机制控制氧化还原状态从过度还原或氧化环境转变为通常破坏与血管生成信号相关的各种调节剂（HO-1，VEGF）。我们认为Peli 1是一个潜在的候选小分子治疗，以管理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.