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.

项目摘要 目前，在美国，有约425,000名患者接受血液透析（HD），据估计是 该人群中有30-60％的人体手术手术后有一些手部功能障碍。基础 造成毁灭性问题的病理生理机制知之甚少。肾 功能障碍（RD）环境导致高清患者的多种生理危险，包括增加 氧化应激（OS）和慢性炎症已被视为加速加速的主要因素 动脉粥样硬化和死亡率升高。 OS的深刻变化有助于骨骼肌和神经肌肉 与该人群中肌肉萎缩和脆弱有关的连接功能障碍。 AVF手术会引起重大 肢体的血液动力学变化提出了对骨骼肌的适应性挑战 神经运动端板。在我们以前的工作以及RD相关骨骼上的初步数据的支持下 肌肉线粒体表型变化，我们提出RD驱动的线粒体功能障碍会改变骨骼 肌肉和神经肌肉连接对AVF诱导的缺血的反应导致临床明显的手 功能障碍。此外，这些途径可以在AVF创建之前修改或最初是手的证据 逆转/防止功能障碍的功能障碍。我们的假设是RD Milieu破坏了 线粒体和细胞能量学，导致OS升高的患者接受AVF手术 发展骨骼肌和神经肌肉连接扰动，导致临床意义 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后，促进了临床上的多样性 明显的手功能障碍。 AIM 1将确定RD如何影响线粒体和细胞能量 AVF引起的肢体缺血加剧。使用一系列体外实验，我们将发现 RD会影响线粒体能量学导致氧化受损的生化机制 磷酸化和OS增加。 AIM 2将决定全球或线粒体靶向的功效 在小鼠AVF手术之前和之后进行的抗氧化剂疗法。使用新颖的RD Murine AVF模型， 我们将确定全球（N-乙酰半胱氨酸）是否为靶向线粒体（线粒体的AAV递送） 靶向过氧化氢酶）抗氧化剂治疗具有AVF诱导的肌肉功能障碍的治疗潜力。目标3 将评估线粒体健康与AVF引起的人体功能障碍之间的关联 患者。线粒体健康将使用RD患者制备的通透性肌纤维对原位进行检查 AVF手术前后 序列血流动力学，神经生理和生物力学结果的变化调节了 将确定手部功能。