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.
Adults with cerebral palsy (CP) are subject to premature declines in muscle function and obesity-related chronic health risk. While the specific mechanisms of these secondary 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. Therefore, the overall purpose of this proposed research and training is to examine the adult CP phenotype from the bedside to the bench, in an effort to distinguish the mechanisms of secondary pathology and comorbidity from those attributable to the primary neuromuscular impairment, and to examine the efficacy of physical activity to improve cardiometabolic health.
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