Melda Onal, Ph. D. Assistant Professor, Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences
“Role of Chaperone Mediated Autophagy in Osteoblast Lineage Cells of the Bone”
Chaperone mediated autophagy (CMA) is a proteolysis mechanism that cells utilize to accommodate cellular stressors such as starvation and oxidative stress. While CMA shares some overlapping functions with macroautophagy, these two autophagy pathways are not redundant and have unique stress response functions. Moreover, CMA has been shown to have cell type specific regulatory functions including contributions to transcriptional regulatory mechanisms. Impairment/decline in CMA has been suggested to contribute to multiple age-related diseases and lysosomal storage disorders such as cystinosis. Interestingly, in a murine cystinosis model, mice develop a low bone mass phenotype despite lack of nephropathy, suggesting a direct effect of the disease in bone
cells, potentially as a result of impaired CMA. However, whether CMA is utilized by bone cells, its physiological functions in bone remodeling or contribution to skeletal pathologies are unknown.
Age-related or genetically-induced increases in oxidative stress have been shown to be associated with apoptosis of osteoblasts (bone forming cells) and osteocytes (cells embedded in the bone matrix that mediate bone formation and resorption), as well as resultant decreases in bone formation and bone mass. As clearance of oxidized proteins is a major function of CMA that has been proposed to be common to all cell types, we hypothesize that “CMA may be a cellular defense mechanism against oxidative stress in osteoblast or osteocytes”. In order to start assessing the role of CMA in these cell types, we propose to:
Aim 1. Determine whether CMA is induced and utilized as a stress response mechanism in osteoblast or osteocyte cell lines.
Aim 2. Perform in vivo loss of function studies to impair CMA and assess the physiological role of CMA in young mice under physiological conditions.
Erin Mannen, Ph.D. Assistant Professor, Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences
“Biomechanics of non-surgically treated infants with developmental hip dysplasia”
Hip instability or developmental dysplasia of the hip (DDH) requires medical treatment for 2/1000 newborns and is typically diagnosed before 6 months of age. Untreated, the condition may progress to cause a lifetime of pain and disability. Early diagnosis and treatment with a Pavlik harness, a 70-year-old solution that holds the baby’s hips in a flexed and abducted position, are key to reducing the hip and solving the DDH problem. However, the baby must wear the harness for 24 hours/day for several weeks, resulting in a unique burden for the motion/caregiver and the infant. While the Pavlik harness is effective in reducing hips in nearly 80% of cases, the biomechanical change that the harness induces is not well understood. Without a clear idea of why and how the brace works to reduce hips, it is impossible to improve upon this basic treatment device. The purpose of this study is to understand the muscle activity and hip positioning changes of DDH infants from successful Pavlik harness treatment and to compare DDH biomechanics with healthy controls to lead to the development of improved DDH therapies.
Aim 1. Quantify change in hip positioning and muscle activity of DDH patients undergoing treatment
Aim 2. Compare lower extremity biomechanics of DDH patients with healthy controls.