Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial
Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial
批准号:
9927974
负责人:
Mary McGrae McDermott
金额:
$20.22万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-15 至 2023-12-31
关键词:
Adverse effectsAgeBiopsyBlood capillariesCell CountCell Differentiation processCellsDataDesire for foodDisabled PersonsDoseEndotheliumFiberGrowthHindlimbHumanIn VitroInjuryInsulin ResistanceInvestigational DrugsIschemiaLimb structureLower ExtremityMediatingMedicalMitochondriaModelingMusMuscleMuscle CellsMuscle FibersMuscle MitochondriaMuscle functionMuscle satellite cellMuscular AtrophyNatural regenerationNew Drug ApprovalsOutcomeParticipantPatientsPerformancePerfusionPeripheral arterial diseasePhenotypePilot ProjectsPlacebosProductionRandomizedSkeletal MuscleSomatotropinSuccinate DehydrogenaseTestingTherapeuticTimeTissuesWalkingWorkangiogenesiscell regenerationdensitydesigneffective therapyfollow-upfunctional declinefunctional disabilitygastric fundusghrelingrowth hormone secretagogue receptorimprovedimproved functioningmitochondrial dysfunctionmouse modelmuscle regenerationmuscular dystrophy mouse modelolder patientpeptide hormonepilot trialpre-clinicalpreventprimary outcomerandomized trialsatellite cellsecondary outcomesubcutaneoustreadmill
中文摘要
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
PAD患者的损失。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。
英文摘要
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.
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