Impaired Mitochondrial Energetics is a Driver of Hemodialysis Access Related Hand Dysfunction

线粒体能量受损是血液透析相关手部功能障碍的驱动因素

• 批准号: 10461804
• 负责人: Salvatore T. Scali
• 金额: $ 53.88万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461804
• 关键词: Acetylcholine; Acetylcysteine; Acute; Aging; Animal Model; Appearance; Arteriovenous fistula; Atherosclerosis; Biochemical; Biogenesis; Biomechanics; Buffers; Cell Culture Techniques; Cell Energetics; Chronic; Clinical; Cultured Cells; Data; Development; Elements; Event; Exposure to; Fistula; Functional disorder; Gangrene; Hand; Hand functions; Health; Hemodialysis; Heterogeneity; Human; Impairment; In Situ; In Vitro; Inflammation; Injury; Ischemia; Lead; Limb structure; Measures; Mediating; Metabolic stress; Mitochondria; Modeling; Motor; Mus; Muscle; Muscle Mitochondria; Muscular Atrophy; Nerve; Neuromuscular Junction; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxygen; Pain; Paraparesis; Paresthesia; Pathologic; Pathway interactions; Patients; Perfusion; Phenotype; Physiological; Physiology; Population; Preventive; Process; Production; Rehabilitation therapy; Sampling; Sensory; Series; Signal Transduction; Skeletal Muscle; Testing; Therapeutic; United States; Work; antioxidant therapy; catalase; clinical phenotype; clinically significant; digital; disability; experimental study; frailty; functional disability; hand dysfunction; hemodynamics; innovation; kidney dysfunction; limb ischemia; mitochondrial dysfunction; mortality; neuromuscular; neurophysiology; novel; novel therapeutics; patient subsets; patient variability; prevent; renal ischemia; repaired; response

PROJECT SUMMARY Currently, in the United States, there are ~425,000 patients receiving hemodialysis (HD) and it is estimated that 30-60% of this population have some element of hand dysfunction after hemoaccess surgery. The underlying pathophysiologic mechanisms responsible for this devastating problem are poorly understood. The renal dysfunction (RD) milieu causes a variety of physiologic derangements in HD patients including increased oxidative stress (OS) and chronic inflammation that have been implicated as major contributors to accelerated atherosclerosis and elevated mortality. Profound changes in OS contribute to skeletal muscle and neuromuscular junction dysfunction associated with muscle atrophy and frailty in this population. AVF surgery causes significant hemodynamic changes in the extremity which presents an adaptive challenge to the skeletal muscle and neuromotor end-plate. Supported by our previous work, as well as preliminary data on RD associated skeletal muscle mitochondrial phenotypic changes, we propose that RD driven mitochondrial dysfunction alters skeletal muscle and neuromuscular junction responses to AVF induced ischemia leading to clinically apparent hand dysfunction. Further, these pathways can be modified either prior to AVF creation or at first evidence of hand dysfunction to reverse/prevent the functional impairment. Our hypothesis is that the RD milieu disrupts mitochondrial and cellular energetics resulting in elevated OS predisposing patients undergoing AVF surgery to developing skeletal muscle and neuromuscular junction perturbations causing clinically significant hand dysfunction. RD mediated mitochondrial impairments are further exacerbated by local hemodynamic changes following AVF creation through maladaptive OS metabolic responses that drives the diversity of clinically apparent hand dysfunction. Aim 1 will establish how RD impacts mitochondrial and cellular energetics that are exacerbated by AVF-induced limb ischemia. Using a series of in vitro experiments, we will uncover the biochemical mechanisms by which RD impacts mitochondrial energetics leading to impaired oxidative phosphorylation and increased OS. Aim 2 will determine the efficacy of global or mitochondrial-targeted antioxidant therapies delivered prior to- and following AVF surgery in mice. Using a novel RD murine AVF model, we will determine whether global (N-acetylcysteine) or mitochondrial-targeted (AAV delivery of mitochondrial targeted catalase) antioxidant therapy have therapeutic potential for AVF-induced muscle dysfunction. Aim 3 will evaluate the association between mitochondrial health and AVF-induced hand dysfunction in human patients. Mitochondrial health will be examined in-situ using permeabilized myofibers prepared from RD patients before and after AVF surgery: mitochondrial phenotypic changes will be evaluated and their association with changes in serial hemodynamic, neurophysiological and biomechanical outcomes modulating the spectrum of hand function will be determined.

项目概要 目前，在美国，大约有 425,000 名患者接受血液透析 (HD)，估计 该人群中 30-60% 的人在血液通路手术后出现某些手部功能障碍。底层的 对于造成这一破坏性问题的病理生理机制知之甚少。肾 功能障碍 (RD) 环境会导致 HD 患者出现多种生理紊乱，包括增加 氧化应激（OS）和慢性炎症被认为是加速的主要原因 动脉粥样硬化和死亡率升高。操作系统的深刻变化有助于骨骼肌和神经肌肉 该人群中与肌肉萎缩和虚弱相关的连接功能障碍。 AVF 手术会导致严重的 四肢的血流动力学变化对骨骼肌提出了适应性挑战 神经运动终板。由我们之前的工作以及 RD 相关骨骼的初步数据支持 肌肉线粒体表型变化，我们认为 RD 驱动的线粒体功能障碍会改变骨骼 肌肉和神经肌肉接头对 AVF 引起的缺血的反应，导致临床上明显的手部症状 功能障碍。此外，这些途径可以在 AVF 创建之前或在手的第一个证据时进行修改 逆转/预防功能障碍的功能障碍。我们的假设是 RD 环境会扰乱 线粒体和细胞能量学导致 OS 升高，使接受 AVF 手术的患者容易出现 发育中的骨骼肌和神经肌肉接头扰动导致临床上显着的手部症状 功能障碍。局部血流动力学变化进一步加剧了 RD 介导的线粒体损伤 通过适应不良的 OS 代谢反应创建 AVF，从而推动临床多样性 明显的手功能障碍。目标 1 将确定 RD 如何影响线粒体和细胞能量学 AVF 引起的肢体缺血会加剧。通过一系列体外实验，我们将揭开 RD影响线粒体能量学导致氧化受损的生化机制 磷酸化和增加 OS。目标 2 将确定全局或线粒体靶向的功效 在小鼠 AVF 手术之前和之后进行抗氧化治疗。使用新型 RD 小鼠 AVF 模型， 我们将确定是全局靶向（N-乙酰半胱氨酸）还是线粒体靶向（AAV 递送线粒体） 靶向过氧化氢酶）抗氧化疗法对 AVF 引起的肌肉功能障碍具有治疗潜力。目标 3 将评估线粒体健康与 AVF 引起的人类手部功能障碍之间的关联 患者。将使用 RD 患者制备的透化肌纤维对线粒体健康状况进行原位检查 AVF 手术前后：将评估线粒体表型变化及其与 一系列血流动力学、神经生理学和生物力学结果的变化调节范围 将确定手部功能。