New therapeutic strategies for Peripheral Arterial Disease

项目总结 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，其特征是 血管退化、缺血、线粒体功能障碍和肢体肌病。经典的血管生成调节剂 如Vegfa，已被证明是治疗干预的主要焦点，在临床上是无效的。 因此，PAD的药物治疗仍然是一个未得到满足的医疗需求，导致肢体瘫痪。 每年有近20万名患者被截肢。康复锻炼已成为一种有效的临床治疗方法。 利用PAD对氧化代谢和血管形成的刺激作用来管理PAD的策略 四肢肌肉系统。然而，物理治疗的一个共同局限性是大多数PAD患者，特别是 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， 运动和糖尿病中代谢和血管重塑的分子调控可能存在 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-)对小鼠代谢能力、血管供应和运动能力的调节 运动、糖尿病和脑缺血。我们还将研究ERR表达的调控机制和 骨骼肌的活动。我们假设：(I)Err负责运动介导的代谢 和骨骼肌血管重塑，(Ii)糖尿病骨骼肌中ERR的过度表达 小鼠在缺乏运动的情况下减轻糖尿病垫样病理，以及(Iii)HIF调节Err的表达和 骨骼肌中的信号。这一假设将在三个目标上得到检验。在目标1中，我们将调查 ERR在调节肢体肌肉代谢和血管特性中的基线和反应 锻炼身体。在目标2中，我们将研究ERR激活是否可以减轻糖尿病患者的PAD样病变 老鼠。在目标3中，我们将研究低氧诱导因子(Hifs)在err调节中的作用。 在骨骼肌中的表达和活性。在这些研究中，我们将使用ERR的肌肉特异性靶向 在转基因小鼠中，以及肌肉注射aAV9-err来检测对运动、糖尿病和 缺血适应。此外，我们将使用细胞力学的方法来进一步阐明代谢和 肌肉ERR对旁分泌血管生成的调节，以及HIF对ERR的调节。我们期待我们的工作 为了证明ERR在运动、糖尿病等疾病中是肌肉代谢和血管容量的中枢调节 和缺血，并强调ERR作为治疗糖尿病相关PAD的潜在候选药物。

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.