New therapeutic strategies for Peripheral Arterial Disease

项目摘要 糖尿病是外周动脉疾病（PAD）的主要原因，PAD是一种心血管并发症，其特征在于 血管退化、局部缺血、线粒体功能障碍和肢体肌病。经典血管生成调节因子 例如Vegfa，其已经成为治疗干预的主要焦点，但已被证明在临床上是无效的。 因此，PAD的药物治疗仍然是未满足的医疗需求，导致肢体瘫痪。 每年有近20万患者接受截肢手术。恢复性运动已成为一种有效的临床 治疗PAD的策略是通过其对氧化代谢和血管化的刺激作用， 四肢肌肉组织然而，物理治疗的一个常见局限性是大多数PAD患者，尤其是 患有糖尿病的人，由于严重的腿部疼痛或其他心血管并发症而不能锻炼。因此，我们认为， 运动和糖尿病中代谢和血管重塑的分子调节特征可能存在 治疗PAD的新靶点。在这项研究中，我们将探讨核受体雌激素相关的作用， 受体α（ERR α）在调节小鼠模型的代谢能力、血管供应和运动能力中的作用 运动、糖尿病和局部缺血。我们还将研究调节ERR β表达的机制， 骨骼肌的活动。我们假设：（I）ERR β是负责运动介导的代谢 糖尿病患者骨骼肌中ERR β的过度表达， 小鼠在缺乏运动的情况下减轻糖尿病PAD样病理，和（III）HIF调节ERR β表达， 骨骼肌中的信号。这个假设将在三个目标中得到检验。在目标1中，我们将研究 ERR β在基线和响应时调节肢体肌肉组织的代谢和血管特征 锻炼身体在目标2中，我们将研究ERR β激活是否可以减轻糖尿病患者的PAD样病理， 小鼠在目的3中，我们将研究缺氧诱导因子（HIF）在ERR基因表达调控中的作用。 在骨骼肌中的表达和活性。对于这些研究，我们将使用肌肉特异性靶向的ERR基因， 在转基因小鼠中，以及肌肉内AAV 9-ERR递送，以检查对运动、糖尿病和 缺血性适应此外，我们将使用细胞机制的方法，以进一步阐明代谢和 通过肌肉ERR β的旁分泌血管生成调节，以及通过HIF调节ERR β。我们希望我们的工作 为了证明ERR β是运动中肌肉代谢和血管容量的中心调节因子，糖尿病 和缺血，并强调ERR作为治疗糖尿病相关PAD的潜在治疗候选物。

PROJECT SUMMARY Diabetes is a leading cause of peripheral arterial disease (PAD), a cardiovascular complication characterized by blood vessel regression, ischemia, mitochondrial dysfunction and limb myopathy. Classic angiogenic regulators such as Vegfa, which have been a major focus of therapeutic interventions have proved to be inefficient clinically. Consequently, pharmacological treatment of PAD has remained an unmet medical need, leading to limb amputations in nearly 200,000 patients every year. Rehabilitative exercise has emerged as an effective clinical strategy for managing PAD by virtue of its stimulatory effects on oxidative metabolism and vascularization in the limb musculature. However, a common limitation of physical therapy is that majority of PAD patients, especially ones with diabetes, cannot exercise due to severe leg pain or other cardiovascular complications. Therefore, characterizing molecular regulation of metabolic and vascular remodeling in exercise and diabetes may present novel targets for treating PAD. In this study, we will investigate the role of nuclear receptor estrogen-related receptor alpha (ERR) in regulating metabolic capacity, vascular supply and exercise capacity in murine models of exercise, diabetes and ischemia. We will also investigate mechanisms regulating ERR expression and activity in the skeletal muscles. We hypothesize that (I) ERR is responsible for exercise-mediated metabolic and vascular remodeling in the skeletal muscle, (II) overexpression of ERR in the skeletal muscles of diabetic mice mitigates diabetic PAD-like pathology in absence of exercise, and (III) HIFs regulate ERR expression and signaling in the skeletal muscle. The hypothesis will be tested in three aims. In Aim 1, we will investigate the role of ERR in regulating metabolic and vascular characteristics of the limb musculature at baseline and in response to exercise. In Aim 2, we will investigate whether ERR activation can mitigate PAD-like pathology in diabetic mice. In Aim 3, we will investigate the function of hypoxia-inducible factors (HIFs) in the regulation of ERR expression and activity in the skeletal muscle. For these studies, we will use muscle-specific targeting of ERR in transgenic mice, as well as intramuscular AAV9-ERR delivery to examine effect on exercise, diabetes and ischemic adaptations. In addition, we will use cellular mechanistic approach to further elucidate metabolic and paracrine angiogenic regulation by muscle ERR, as well as regulation of ERR by HIFs. We expect our work to demonstrate that ERR is a central regulator of muscle metabolic and vascular capacity in exercise, diabetes and ischemia, and highlight ERR as a potential therapeutic candidate for treating diabetes-associated PAD.