New therapeutic strategies for Peripheral Arterial Disease

周围动脉疾病的新治疗策略

基本信息

批准号：
10662261
负责人：
VIHANG A NARKAR
金额：
$ 44.46万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662261
关键词：
Activities of Daily Living Aerobic Aerobic Exercise Amputation Angiogenic Factor Blood Vessels Brain Hypoxia-Ischemia Cardiovascular system Cell Respiration Cells Characteristics Clinical Complication Complications of Diabetes Mellitus Coupled Development Diabetes Mellitus Diabetic mouse ERR1 protein Estrogen Nuclear Receptor Exercise Exercise Therapy Exercise Tolerance Fiber Functional disorder Gene Expression Gene Expression Regulation Genes Glucose Intolerance HIF1A gene Hindlimb Hyperglycemia Hypoxia Hypoxia Inducible Factor Impairment Injections Intervention Intramuscular Ischemia Knock-out Knockout Mice Laboratories Lead Limb structure Link Mediating Mediator Medical Metabolic Metabolism Mitochondria Molecular Mus Muscle Muscle Fibers Muscle function Myopathy Names Nuclear Orphan Receptor Pain in lower limb Pathology Patients Perfusion Peripheral arterial disease Pharmacological Treatment Physical therapy Recovery Recovery of Function Regulation Regulatory Pathway Rehabilitation therapy Repression Respiration Role Running Signal Transduction Skeletal Muscle Stimulus Testing Therapeutic Intervention Transgenic Mice Vascular Endothelial Growth Factors Vascular blood supply Vascular remodeling Vascularization Work angiogenesis comorbidity diabetic exercise capacity exercise intolerance exercise rehabilitation exercise training insight knock-down limb amputation mimetics mitochondrial dysfunction mouse model novel novel therapeutic intervention overexpression paracrine pharmacologic programs response skeletal muscle metabolism therapeutic candidate therapeutic target transcriptome sequencing vessel regression

项目摘要

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.

项目概要糖尿病是外周动脉疾病（PAD）的主要原因，外周动脉疾病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。例如 Vegfa，它一直是治疗干预的主要焦点，但在临床上已被证明效率低下。经过测试，PAD 的药物治疗仍然是一个未满足的医疗需求，导致肢体每年有近20万名患者接受截肢手术，康复锻炼已成为一种有效的临床方法。凭借其对氧化代谢和血管形成的刺激作用来管理 PAD 的策略然而，物理治疗的一个常见限制是大多数 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无法运动。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，我们将研究核受体雌激素相关的作用。受体 α (ERR) 在小鼠模型中调节代谢能力、血管供应和运动能力我们还将研究调节 ERR 表达和缺血的机制。我们勇敢地承认 (I) ERR 负责运动介导的代谢。和骨骼肌中的血管重塑，（II）糖尿病患者骨骼肌中ERRα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，并且 (III) HIF 调节 ERRα 表达并在目标 1 中，我们将研究骨骼肌中的信号传导的作用。 ERR 在调节基线和响应时肢体肌肉组织的代谢和血管特征中的作用在目标 2 中，我们将研究 ERR 激活是否可以减轻糖尿病患者的 PAD 样病理。在目标 3 中，我们将研究缺氧诱导因子 (HIF) 在调节 ERR 中的功能。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 来检查对运动、糖尿病和此外，我们将使用细胞机制方法进一步阐明代谢和适应。肌肉 ERRα 的旁分泌血管生成调节以及 HIF 对 ERRα 的调节我们期待我们的工作。证明 ERR 是运动、糖尿病中肌肉代谢和血管容量的中央调节剂和缺血，并强调 ERR 作为治疗糖尿病相关 PAD 的潜在治疗候选者。