Secondary Muscle Pathology & Metabolic Dysregulation in Adult with Cerebral Palsy

继发性肌肉病理学

• 批准号: 8421813
• 负责人: Mark D Peterson
• 金额: $ 12.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8421813
• 关键词: Adipose tissue; Adult; Award; Awareness; Behavior; Biogenesis; Biological Markers; Biopsy; Body Composition; Cellular Morphology; Cerebral Palsy; Child; Chronic; Chronic Disease; Clinic; Clinical; Clinical Research; Comorbidity; Data; Data Collection; Deterioration; Dietary Intervention; Discipline; Disease; Dose; Drug or chemical Tissue Distribution; Dual-Energy X-Ray Absorptiometry; Dyslipidemias; Effectiveness; Ensure; Enzyme-Linked Immunosorbent Assay; Enzymes; Etiology; Event; Exercise Physiology; Extracellular Matrix; Faculty; Familiarity; Fatigue; Fibrosis; Flow Cytometry; Foundations; Functional disorder; General Population; Goals; Health; Hemiplegia; High Prevalence; Hyperlipidemia; Hypertension; Image; Impairment; Individual; Inflammation; Insulin Resistance; Intervention; Intervention Studies; Learning; Magnetic Resonance Imaging; Measures; Mediating; Mentored Research Scientist Development Award; Mentors; Metabolic; Michigan; Mitochondria; Modeling; Monitor; Morphology; Muscle; Muscle Spasticity; Muscle function; Muscular Atrophy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Pathology; Pathway interactions; Patients; Phenotype; Physical activity; Polymerase Chain Reaction; Population; Prevalence; Preventive; Procedures; Proteins; Protocols documentation; Public Health; Quality of life; Radiology Specialty; Reactive Oxygen Species; Rehabilitation Research; Rehabilitation therapy; Research; Research Personnel; Research Training; Risk; Sampling; Serum; Severities; Skeletal Muscle; Solid; Spastic; Spinal cord injury; Staining method; Stains; Surveillance Program; Symptoms; Techniques; Time; Tissues; Training; Transcriptase; Western Blotting; Work; bench to bedside; career; clinically relevant; cytokine; data management; design; disability; disorder risk; fitness; functional decline; glucose transport; health disparity; improved; in vivo; inflammatory marker; insulin sensitivity; insulin signaling; intravenous glucose tolerance test; macrophage; member; middle age; motor impairment; muscle form; national surveillance; neuromuscular; obesity risk; premature; programs; public health relevance; research study; sedentary; sex; skeletal; skills; social; subcutaneous

DESCRIPTION (provided by applicant): Premature declines in function among adults with cerebral palsy (CP) may occur as a result of early and accelerated weakness, beyond that which is expected for adults in the general population. While the specific mechanisms of secondary muscle pathology and related comorbidities are not well defined, ample evidence exists to confirm that individuals with CP have lower fitness, less muscle mass, neuromuscular inefficiency, and significantly reduced functional reserve throughout the span of adulthood. This ongoing circular cause and consequence of events leads to a debilitating loss of muscle function and impaired morphology, as well as an exaggerated risk for obesity and cardiometabolic disease. Therefore, the overall purpose of this training and research is to examine the adult CP phenotype from the bedside to the bench with the explicit intent to distinguish and target the mechanisms of secondary comorbidity from those attributable to the primary neuromuscular impairment. The candidate has a strong professional background in exercise physiology, and has worked with a variety of populations and spectrum of clinical needs. His career goal is to develop a medical rehabilitation research program for targeting muscle dysfunction and cardiometabolic health among individuals with CP. This long- term objective will require coursework and intensive bench training in integrative pathophysiology of obesity and muscle spasticity, as well as in clinical and biostatistical aspects specific to the treatment/study of CP. The Mentored Research Scientist Development Award will prepare the candidate as an independent medical rehabilitation investigator through the following short-term directives: (1) To acquire a comprehensive expertise of the pathways associated with obesity and metabolic dysregulation, as well as those associated with aberrant adaptations to chronic sedentary behavior and muscle spasticity; (2) To gain an in-depth understanding of the specific clinical aspects of CP, including issues pertaining to severity of motor impairment and quality of life, the negative influence of treatments on health and activity, and how impairment effects social participation and health disparity; and (3) To develop the technical and statistical skills to conduct specialized imaging for quantifying skeletal muscle and adipose tissue, serum and in vivo studies for markers of inflammation and insulin resistance, and immunohistochemical quantification and polymerase chain reaction studies of skeletal muscle and adipose tissue. Achieving these short-term directives during the award period will also build a solid foundation for each of the candidate's long-term career goals which include: (1) To conduct experiments to identify the discrete cellular etiology of fibro-adipose degeneration of skeletal muscles and metabolic dysregulation among sedentary individuals with CP; (2) To conduct a program of preventive health research through tailored physical activity and dietary interventions for children and adults with CP; and (3) To bolster public health awareness regarding chronic disease risks for specific sub-populations with disabilities. The candidate will train with a group of internationally renowned mentors and collaborators from 6 disciplines to gain content expertise, and to learn specific data collection techniques for identifying morphological and cellular differences in skeletal muscle and adipose tissue between adults with and without CP, as well as within spastic and non-spastic muscle. The primary aim of the study was designed with a clinically-oriented purpose to compare cardiometabolic profiles among adults with CP and matched adult controls. For this aim the candidate will work with 1) Dr. Horowitz to learn and perform frequently sampled intravenous glucose tolerance tests on all subjects in this study, 2) Michigan Clinical Research Unit (MCRU) to learn dual-energy X-ray absorptiometry quantification of whole body and regional body composition, 3) Dr. Chenevert in Radiology to learn skeletal muscle and adipose tissue volume and fractional quantification, using the MRI Dixon protocol, and 4) Drs. Burant and Gordon to become familiar analyzing cardiometabolic serum and tissue biomarkers. The second aim was designed to assess the effectiveness of low-dose physical activity on cardiometabolic parameters among adults with CP, and to determine the extent to which changes are mediated by alterations in adiposity. The candidate will work with 1) Dr. Gordon and members of the PAEIR Lab to learn the necessary skills for directing a clinical intervention study and 2) Dr. Hurvitz and staff from the UM Adult C clinic to ensure patients' needs are being recognized and symptoms are handled appropriately. For the third aim, the candidate will examine within-subjects transcriptional and cellular morphological differences in spastic versus non-spastic muscle from sedentary adults with hemiplegic CP, and to contrast with non-CP controls. Successful completion of aim 3 will require the candidate to spend ample time working with Drs. Burant and Gordon, and faculty of the MNORC to learn various immunohistochemical procedures. Throughout the entirety of training, the candidate will also work with Dr. Spino for data management and biostatistical expertise.

描述（由申请人提供）：脑瘫（CP）成人的功能过早衰退可能是由于早期和加速的虚弱导致的，超出了一般人群中成年人的预期。虽然继发性肌肉病理学和相关合并症的具体机制尚未明确，但有充分的证据证实，患有 CP 的个体在整个成年期的健康状况较低、肌肉质量较少、神经肌肉效率低下以及功能储备显着降低。这种持续循环的事件因果关系会导致肌肉功能丧失和形态受损，以及肥胖和心脏代谢疾病的风险增大。因此，本次培训和研究的总体目的是从床边到工作台检查成人 CP 表型，明确意图区分和针对继发性合并症与原发性神经肌肉损伤的机制。 该候选人在运动生理学方面拥有强大的专业背景，并曾与各种人群和临床需求进行过合作。他的职业目标是开发一项针对脑瘫患者肌肉功能障碍和心脏代谢健康的医疗康复研究计划。这一长期目标将需要在肥胖和肌肉痉挛的综合病理生理学以及针对脑瘫治疗/研究的临床和生物统计学方面进行课程作业和强化台架训练​​。指导研究科学家发展奖将通过以下短期指导，帮助候选人成为一名独立的医疗康复研究者：（1）获得与肥胖和代谢失调相关的途径的全面专业知识，以及与慢性久坐行为和肌肉痉挛的异常适应相关的途径； (2) 深入了解脑瘫的具体临床情况，包括 与运动损伤的严重程度和生活质量、治疗对健康和活动的负面影响以及运动损伤如何影响社会参与和健康差异有关的问题； (3) 发展技术和统计技能，以进行专门成像以量化骨骼肌和脂肪组织、炎症和胰岛素抵抗标志物的血清和体内研究，以及骨骼肌和脂肪组织的免疫组织化学量化和聚合酶链反应研究。在颁奖期间实现这些短期指示也将为每位候选人的长期职业目标奠定坚实的基础，其中包括：（1）进行实验以确定久坐的脑瘫患者骨骼肌纤维脂肪变性和代谢失调的离散细胞病因学； (2) 通过针对脑瘫儿童和成人量身定制的身体活动和饮食干预措施，开展预防性健康研究计划； (3) 提高公众对特定残疾人群慢性病风险的认识。 候选人将与来自 6 个学科的国际知名导师和合作者一起进行培训，以获得内容专业知识，并学习特定的数据收集技术，以识别患有和不患有 CP 的成年人之间以及痉挛和非痉挛肌肉内骨骼肌和脂肪组织的形态和细胞差异。该研究的主要目的是以临床为导向的目的，比较 CP 成人和匹配成人对照的心脏代谢特征。为此，候选人将与 1) Horowitz 博士合作，学习并针对本研究中的所有受试者进行频繁采样的静脉葡萄糖耐量测试，2) 密歇根临床研究单位 (MCRU) 学习全身和局部身体成分的双能 X 射线吸收测定法量化，3) 放射学的 Chenevert 博士学习骨骼肌和脂肪组织体积和分数量化， 使用 MRI Dixon 协议，以及 4) 博士。 Burant 和 Gordon 开始熟悉心脏代谢血清和组织生物标志物的分析。第二个目的是评估低剂量体力活动对成人脑瘫患者心脏代谢参数的影响，并确定肥胖改变在多大程度上介导变化。候选人将与 1) Gordon 博士和 PAEIR 实验室成员合作，学习指导临床干预研究的必要技能；2) Hurvitz 博士和 UM Adult C 诊所的工作人员，确保患者的需求得到认可，症状得到适当处理。对于第三个目标，候选人将检查患有偏瘫性 CP 的久坐成年人的痉挛与非痉挛肌肉的受试者体内转录和细胞形态差异，并与非 CP 对照进行对比。成功完成目标 3 将要求候选人花充足的时间与 Drs. 一起工作。 Burant 和 Gordon 以及 MNORC 的教员学习各种免疫组织化学程序。在整个培训过程中，候选人还将与 Spino 博士一起学习数据管理和生物统计专业知识。