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）：由于早期和加速弱点，可能发生脑瘫（CP）的成年人的功能过早，超出了普通人群中成年人的预期。虽然次要肌肉病理学和相关合并症的特定机制尚未得到很好的定义，但存在充足的证据以确认患有CP的人的适应性较低，肌肉质量较低，神经肌肉效率低下，并且在整个成年期间的功能储备显着降低。事件的这种持续的循环原因和结果导致肌肉功能的丧失和形态受损，以及肥胖和心脏代谢疾病的夸张风险。因此，这项培训和研究的总体目的是检查从床边到板凳的成年CP表型，以明确的意图，以区分和靶向二次合并症的机制与可归因于主要神经肌肉障碍的次级合并症的机制。 该候选人在运动生理学方面具有强大的专业背景，并与各种临床需求的人群和范围合作。他的职业目标是制定一项医疗康复研究计划，以针对CP患者中的肌肉功能障碍和心脏代谢健康。这个长期目标将需要肥胖和肌肉痉挛的综合病理生理学以及CP治疗/研究特定的临床和生物统计方面的综合病理生理学培训。指导的研究科学家发展奖将通过以下短期指令为候选人作为独立的医疗康复研究者做好准备：（1）获得与肥胖和代谢失调相关的途径的全面专业知识，以及与对长期耐久性行为和肌肉痉挛性持久适应的途径； （2）对CP的具体临床方面有深入的了解，包括 与运动障碍和生活质量严重程度有关的问题，治疗对健康和活动的负面影响以及损害如何影响社会参与和健康差异； （3）开发技术和统计技能，以进行专门的成像，以量化骨骼肌肉和脂肪组织，血清和体内研究，以进行炎症和胰岛素抵抗的标志物，以及免疫组织化学定量和聚合酶链链链链反应研究的骨骼肌和脂肪组织和脂肪组织。在奖励期内实现这些短期指令还将为每个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，以确定骨骼肌肉肌肉肌肉脂肪变性的离散细胞病因和CP的久代代谢失调； （2）通过针对CP的儿童和成人进行量身定制的体育活动和饮食干预措施来进行预防健康研究的计划； （3）增强公共卫生对特定残疾亚人群的慢性疾病风险的认识。 候选人将与来自6个学科的国际知名导师和合作者进行培训，以获取内容专业知识，并学习特定的数据收集技术，以识别具有和没有CP的成年人之间的骨骼肌和脂肪组织的形态和细胞差异，以及痉挛性和非痉挛性肌肉。该研究的主要目的是设计具有临床为导向的目的，以比较具有CP和匹配的成人对照组的成年人中的心脏代谢谱。 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,使用MRI Dixon协议和4）DRS。 Burant和Gordon熟悉分析心脏代谢血清和组织生物标志物。第二个目的旨在评估低剂量体育活动对CP成年人心脏代谢参数的有效性，并确定肥胖改变介导的变化的程度。候选人将与1）Gordon博士和Paeir Lab的成员一起学习指导临床干预研究的必要技能，以及2）Hurvitz博士和UM成人C诊所的工作人员和工作人员，以确保认识到患者的需求并适当处理症状。为了第三个目标，候选人将检查受试者内部和细胞形态学差异的痉挛性肌肉与非痉挛性肌肉的久坐成年人，并与非CP对照组对比。成功完成AIM 3将要求候选人花足够的时间与DRS合作。 Burant和Gordon，以及MNORC的学院学习各种免疫组织化学程序。在整个培训中，候选人还将与Spino博士合作，以获得数据管理和生物统计学专业知识。