Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial

非酰化 Ghrelin 改善 PAD 功能：GIFT 试验

• 批准号: 9927974
• 负责人: Mary McGrae McDermott
• 金额: $ 20.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927974
• 关键词: Adverse effects; Age; Biopsy; Blood capillaries; Cell Count; Cell Differentiation process; Cells; Data; Desire for food; Disabled Persons; Dose; Endothelium; Fiber; Growth; Hindlimb; Human; In Vitro; Injury; Insulin Resistance; Investigational Drugs; Ischemia; Limb structure; Lower Extremity; Mediating; Medical; Mitochondria; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscle Mitochondria; Muscle function; Muscle satellite cell; Muscular Atrophy; Natural regeneration; New Drug Approvals; Outcome; Participant; Patients; Performance; Perfusion; Peripheral arterial disease; Phenotype; Pilot Projects; Placebos; Production; Randomized; Skeletal Muscle; Somatotropin; Succinate Dehydrogenase; Testing; Therapeutic; Time; Tissues; Walking; Work; angiogenesis; cell regeneration; density; design; effective therapy; follow-up; functional decline; functional disability; gastric fundus; ghrelin; growth hormone secretagogue receptor; improved; improved functioning; mitochondrial dysfunction; mouse model; muscle regeneration; muscular dystrophy mouse model; older patient; peptide hormone; pilot trial; pre-clinical; prevent; primary outcome; randomized trial; satellite cell; secondary outcome; subcutaneous; treadmill

Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial Our work and that of others shows that patients with lower extremity peripheral artery disease (PAD) have greater functional impairment, faster functional decline, and higher rates of mobility loss compared to people without PAD. In patients with PAD, ischemia results in calf muscle injury that includes myofiber loss and calf muscle mitochondrial dysfunction. Therapies to regenerate calf skeletal muscle cells, improve mitochondrial function, and increase calf muscle capillary density may improve functioning and prevent mobility loss in people with PAD. Yet few effective therapies currently exist for patients with PAD. This pilot study will investigate the therapeutic potential of unacylated ghrelin to promote capillary growth, increase calf muscle perfusion, and reverse PAD-related skeletal muscle abnormalities, thereby improving PAD-related functional impairment. Ghrelin is a peptide and hormone that circulates in acylated and unacylated forms. Unacylated ghrelin promotes skeletal muscle cell regeneration, improves mitochondrial function, and increases muscle capillary density. Unlike acylated ghrelin, unacylated ghrelin does not increase appetite, or cause insulin resistance. The proposed GIFT Trial will provide preliminary data to test our hypothesis that unacylated ghrelin improves walking performance and prevents mobility loss in older patients with PAD. We further hypothesize that the favorable effect of unacylated ghrelin will be mediated by increased myofiber regeneration, increased muscle capillary density, and improved muscle mitochondria function. If our preliminary data support our hypotheses, results will be used to design a large randomized trial of unacylated ghrelin therapy, in subsequent study, to improve functioning and prevent mobility loss in older people with PAD. We will conduct a pilot randomized trial in 30 participants age 60 and older with PAD, to gather preliminary evidence about whether daily subcutaneously administered unacylated improves the six-minute walk distance (primary outcome), maximal treadmill walking distance (secondary outcome), and calf muscle perfusion (secondary outcome), compared to placebo. We will also perform calf muscle biopsies at baseline and follow up to determine whether unacylated ghrelin increases Type 1 skeletal muscle myofibers, satellite cell number, capillary density, and succinate dehydrogenase (SDH) mitochondrial activity in calf skeletal muscle, compared to placebo. If our hypotheses are correct, results will be used to design a large, definitive randomized trial of unacylated ghrelin to improve lower extremity functioning and prevent mobility loss in the large and growing number of older people who are disabled by PAD.

非酰化Ghrelin改善PAD功能：GIFT试验 我们的工作和其他人的工作表明，下肢外周动脉疾病（PAD）患者 功能障碍更大，功能下降更快，与 没有PAD的人在PAD患者中，缺血导致小腿肌肉损伤，包括肌纤维损失 和小腿肌肉线粒体功能障碍。治疗再生小牛骨骼肌细胞，改善 线粒体功能，并增加小腿肌肉毛细血管密度可以改善功能，防止流动性 在PAD患者中的损失。然而，目前对于PAD患者几乎没有有效的治疗方法。 这项初步研究将探讨非酰化生长激素释放肽促进毛细血管扩张的治疗潜力。 生长，增加小腿肌肉灌注，并逆转PAD相关的骨骼肌异常，从而 改善PAD相关的功能障碍。Ghrelin是一种肽和激素，其以酰化和非酰化形式循环。 未酰化的形式。非酰化ghrelin促进骨骼肌细胞再生，改善线粒体 功能，并增加肌肉毛细血管密度。与酰化生长素释放肽不同，非酰化生长素释放肽不增加 食欲不振，或引起胰岛素抵抗。 拟议的GIFT试验将提供初步数据，以检验我们的假设，即非酰化生长激素释放肽 改善老年PAD患者的行走能力，防止活动能力丧失。我们进一步假设 未酰化的生长素释放肽的有利作用将通过增加肌纤维再生、增加肌纤维再生和增加肌纤维再生来介导。 肌肉毛细血管密度，并改善肌肉线粒体功能。如果我们的初步数据支持 假设，结果将用于设计一个大型随机试验的非酰化生长激素释放肽治疗，在随后的 研究，以改善功能和预防残疾老年人的行动能力丧失。 我们将在30名年龄在60岁及以上的PAD参与者中进行一项试点随机试验， 关于每天皮下注射未酰化的药物是否能改善6分钟 步行距离（主要结局）、最大踏车步行距离（次要结局）和小腿肌肉 灌注（次要结局），与安慰剂相比。我们还将在基线时进行小腿肌肉活检 并随访以确定未酰化的ghrelin是否增加1型骨骼肌肌纤维，卫星 细胞数、毛细血管密度和线粒体琥珀酸脱氢酶（SDH）活性 与安慰剂相比。如果我们的假设是正确的，结果将被用来设计一个大型的，明确的 非酰化生长激素释放肽改善下肢功能和预防活动性丧失的随机试验 由于PAD而致残的老年人数量庞大且不断增加。