Secondary Muscle Pathology & Metabolic Dysregulation in Adult with Cerebral Palsy

继发性肌肉病理学

• 批准号: 9306889
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306889
• 关键词: Adipose tissue; Adult; Award; Awareness; Biogenesis; Biological Markers; Biometry; 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; Genetic Transcription; Goals; Health; Hemiplegia; High Prevalence; Hyperlipidemia; Hypertension; Image; Impairment; Individual; Inflammation; Insulin Resistance; International; 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; Training; Transcriptase; Western Blotting; Work; bench to bedside; cardiometabolic risk; career; clinically relevant; cytokine; data management; design; disability; disorder risk; experimental study; 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; sedentary; sedentary lifestyle; sex; skeletal; skills; social engagement; spasticity; subcutaneous; tissue biomarkers

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）患者的功能过早下降可能是早期和加速衰弱的结果，超出了一般人群中成年人的预期。虽然继发性肌肉病理和相关合并症的具体机制尚不明确，但有充分的证据证实，CP患者在整个成年期的适应度较低，肌肉量较少，神经肌肉效率低下，功能储备显著减少。这种持续循环的原因和后果导致肌肉功能衰弱和形态受损，以及肥胖和心脏代谢疾病的风险夸大。因此，本次培训和研究的总体目的是检查成人CP从床边到台前的表型，明确目的是区分继发性合并症与原发性神经肌肉损伤的机制。