Mitochondrial dysfunction, oxidative damage and inflammation in claudication

跛行时的线粒体功能障碍、氧化损伤和炎症

基本信息

批准号：
8723021
负责人：
Iraklis Ilias Pipinos
金额：
$ 105.04万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723021
关键词：
Adopted Affect Age-Years American Arterial Occlusive Diseases Arteries Atherosclerosis Biochemical Bioenergetics Biomechanics Biopsy Blood flow Caring Characteristics Clinical Clinical assessments Complex Data Diagnosis Disease Disease Progression Elderly Evaluation Event Exercise Functional disorder Future Gait Gait abnormality Gangrene Gastrocnemius Muscle Generations Goals Health Impairment Individual Inflammation Intermittent Claudication Intervention Ischemia Laboratories Laboratory Study Leg Life Style Limb structure Lower Extremity Magnetic Resonance Spectroscopy Measurement Measures Metabolic Mitochondria Modality Modeling Muscle Myalgia Myopathy Needle biopsy procedure Older Population Outcome Oxidative Stress Oxygen Pain Patients Perfusion Peripheral arterial disease Phosphorus Physical activity Physical therapy exercises Physiology Positioning Attribute Prevention Procedures Proteomics Protocols documentation Publications Quality of life Reactive Oxygen Species Regimen Rehabilitation therapy Residual state Rest Risk Series Severities Skeletal Muscle Specimen Staging Staging System Symptoms System Therapeutic Therapeutic Intervention Time Trees Vascular blood supply Walking Work aggressive therapy base claudication clinical care cohort conventional therapy disability experience gait examination hemodynamics improved mitochondrial dysfunction novel diagnostics operation oxidative damage programs public health relevance restoration sedentary tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Claudication, defined as walking-induced leg discomfort and gait dysfunction relieved by rest, affects 5% of Americans over 55 years of age. Claudicating patients adopt sedentary lifestyles and cluster at the extreme low end of the physical activity spectrum, escalating risk for adverse health effects. The primary therapeutic goals for claudicating patients are restoration of leg function and prevention of disease progression. Current, rehabilitative interventions focus on inadequate blood flow as the only cause of claudication. Operative revascularization and/or exercise therapy are the principal conventional therapeutic modalities, providing only modest rehabilitative benefit. Applying biomechanical analysis to gait of claudicating patients, our team has developed preliminary data indicating that blood flow is not the only mechanism producing the limb dysfunction of claudication. Several laboratories including our own have demonstrated a myopathy, characterized by mitochondrial dysfunction, oxidative damage and inflammation, in leg skeletal muscle of claudicating patients. These conditions have not been quantified, comprehensively, in relation to claudication, and their association with severity of claudication is not known. Our hypothesis is that blood flow restriction is not a good predictor of limb dysfunction in claudication, whereas muscle mitochondrial dysfunction, oxidative damage and inflammation are strong predictors of limb dysfunction both at baseline and after conventional therapy with revascularization or supervised exercise. Under Aim #1, we will acquire precise measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation in claudicating patients, at the time of their initial presentation, and evaluate these measurements as predictors of objective measures of limb function and subjective measures of quality of life. Under Aims #2 and #3, we will evaluate the effects of revascularization (Aim#2) and supervised exercise therapy (Aim#3) on mitochondrial dysfunction, oxidative damage and inflammation in claudicating gastrocnemius and on objective measures of limb function and subjective measures of quality of life. If our hypothesis is correct, the work in Aim #2 will for the first time definitively demonstrate that blood flow restriction due to blockages in the arterial tree is not the only cause of claudication. The work under Aims #2 and #3 will determine whether revascularization or exercise therapy has a beneficial effect on the myopathy of claudicating muscle with associated improvement in limb function and quality of life. Finally, the proposed studies under Aims #1, #2 and #3 will provide quantitative modeling of a panel of mechanistic (bioenergetics, oxidative stress and inflammation) parameters as predictors of objective measurements of claudicating limb function and subjective measures of quality of life commonly used for clinical assessment. Measurements of gastrocnemius mitochondrial function, oxidative damage and inflammation may be useful tools that permit staging of disease for optimum intervention and evaluation of therapeutic interventions that specifically target these conditions, improving rehabilitative outcomes.

描述（由申请人提供）：跛行的定义是行走引起的腿部不适和步态功能障碍，可通过休息缓解，影响 5% 的 55 岁以上美国人。跛行患者采取久坐的生活方式，并且集中在体力活动范围的极低端，从而增加了对健康造成不良影响的风险。跛行患者的主要治疗目标是恢复腿部功能和预防疾病进展。目前，康复干预措施的重点是血流不足，这是跛行的唯一原因。手术血运重建和/或运动疗法是主要的常规治疗方式，仅提供适度的康复益处。我们的团队将生物力学分析应用于跛行患者的步态，初步数据表明血流并不是产生跛行肢体功能障碍的唯一机制。包括我们自己的实验室在内的多个实验室已经证明，跛行患者的腿部骨骼肌存在肌病，其特征是线粒体功能障碍、氧化损伤和炎症。这些状况与跛行的关系尚未得到全面量化，并且它们与跛行严重程度的关系尚不清楚。我们的假设是，血流限制并不是跛行时肢体功能障碍的良好预测因子，而肌肉线粒体功能障碍、氧化损伤和炎症是肢体功能障碍的强预测因子，无论是在基线还是在血运重建或监督运动的常规治疗后。根据目标#1，我们将在跛行患者初次就诊时获得腓肠肌线粒体功能、氧化损伤和炎症的精确测量值，并评估这些测量值作为肢体功能客观测量值和生活质量主观测量值的预测因子。在目标#2和#3下，我们将评估血运重建（目标#2）和监督运动疗法（目标#3）对跛行腓肠肌线粒体功能障碍、氧化损伤和炎症的影响，以及对肢体功能客观测量和主观测量的影响生活质量。如果我们的假设是正确的，目标#2 中的工作将首次明确证明，由于动脉树阻塞导致的血流限制并不是跛行的唯一原因。目标 #2 和 #3 下的工作将确定血运重建或运动疗法是否对跛行肌肌病具有有益作用，并改善肢体功能和生活质量。最后，目标#1、#2和#3下拟议的研究将提供一组机械（生物能量学、氧化应激和炎症）参数的定量模型，作为跛行肢体功能客观测量和生活质量主观测量的预测因子用于临床评估。腓肠肌线粒体功能、氧化损伤和炎症的测量可能是有用的工具，可以对疾病进行分期，以实现最佳干预和评估专门针对这些病症的治疗干预措施，从而改善康复结果。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The appropriate use of approximate entropy and sample entropy with short data sets.

DOI：
10.1007/s10439-012-0668-3
发表时间：
2013-03
期刊：
Annals of biomedical engineering
影响因子：
3.8
作者：
Yentes JM;Hunt N;Schmid KK;Kaipust JP;McGrath D;Stergiou N
通讯作者：
Stergiou N

Effects of carotid artery stenting on arterial geometry.

DOI：
10.1016/j.jamcollsurg.2013.03.016
发表时间：
2013-08
期刊：
Journal of the American College of Surgeons
影响因子：
5.2
作者：
A. Kamenskiy;I. Pipinos;Y. Dzenis;J. Bikhchandani;Prateek K. Gupta;Nicholas Y Phillips;S. A. Kazmi;J. MacTaggart
通讯作者：
A. Kamenskiy;I. Pipinos;Y. Dzenis;J. Bikhchandani;Prateek K. Gupta;Nicholas Y Phillips;S. A. Kazmi;J. MacTaggart

Pharmacological treatment of intermittent claudication does not have a significant effect on gait impairments during claudication pain.

间歇性跛行的药物治疗对跛行疼痛期间的步态障碍没有显着效果。

DOI：
10.1123/jab.28.2.184
发表时间：
2012
期刊：
Journal of applied biomechanics
影响因子：
1.4
作者：
Yentes,JenniferM;Huisinga,JessieM;Myers,SaraA;Pipinos,IraklisI;Johanning,JasonM;Stergiou,Nicholas
通讯作者：
Stergiou,Nicholas

Transforming growth factor-beta 1 produced by vascular smooth muscle cells predicts fibrosis in the gastrocnemius of patients with peripheral artery disease.

DOI：
10.1186/s12967-016-0790-3
发表时间：
2016-02-04
期刊：
Journal of translational medicine
影响因子：
7.4
作者：
Ha DM;Carpenter LC;Koutakis P;Swanson SA;Zhu Z;Hanna M;DeSpiegelaere HK;Pipinos II;Casale GP
通讯作者：
Casale GP

Patient Compliance With Wearing Lower Limb Assistive Devices: A Scoping Review.

DOI：
10.1016/j.jmpt.2022.04.003
发表时间：
2022-03
期刊：
JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS
影响因子：
1.3
作者：
Bashir, Ayisha Z.;Dinkel, Danae M.;Pipinos, Iraklis I.;Johanning, Jason M.;Myers, Sara A.
通讯作者：
Myers, Sara A.