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.

项目摘要糖尿病是周围动脉疾病（PAD）的主要原因，这是一种心血管并发症，其为特征血管回归，缺血，线粒体功能障碍和肢体肌病。经典的血管生成调节剂诸如VEGFA（一直是治疗干预措施的主要重点）已被证明在临床上效率低下。因此，PAD的药物治疗仍然是未满足的医疗需求，导致肢体每年将近20万名患者的截肢。康复运动已成为有效的临床通过对氧化代谢和血管形成的刺激作用来管理PAD的策略肢体肌肉。但是，物理治疗的一个普遍局限性是大多数PAD患者，尤其是患有糖尿病的患者由于严重的腿部疼痛或其他心血管并发症而无法运动。所以，表征运动和糖尿病中代谢和血管重塑的分子调节治疗垫的新目标。在这项研究中，我们将研究核接收器雌激素相关的作用鼠模型中的调节代谢能力，血管供应和运动能力的受体α（ERRRIT）我们还将调查调节ERR表达和的机制骨骼肌的活性。我们假设（i）Err负责运动介导的代谢和骨骼肌中的血管重塑，（ii）糖尿病骨骼肌肉中Err的过表达在没有运动的情况下，小鼠减轻糖尿病垫状病理，（iii）HIF调节ERR表达和骨骼肌发出信号。该假设将以三个目标进行检验。在AIM 1中，我们将调查角色在控制基线和反应时肢体肌肉的代谢和血管特征方面锻炼。在AIM 2中，我们将调查ERR激活是否可以减轻糖尿病中的类似垫状病理老鼠。在AIM 3中，我们将研究缺氧诱导因素（HIF）在ERRA调节中的功能骨骼肌的表达和活性。对于这些研究，我们将使用ERR的肌肉特异性靶向在转基因小鼠以及肌肉内AAV9-ERR递送到运动对运动的影响，糖尿病和缺血性适应。此外，我们将使用细胞机械方法来进一步阐明代谢和通过肌肉ERR以及HIF的ERRRE调节，旁分泌血管生成。我们期望我们的工作为了证明ERRR是运动中肌肉代谢和血管能力的中心调节剂和缺血，并突出显示了治疗糖尿病相关垫的潜在治疗候选者。