CAREER: Multiscale Osmotic Mechanotransduction within the Intervertebral Disc

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This Faculty Early Career Development (CAREER) award focuses on understanding how mechanical loads applied to the spine regulate cellular function in health and disease. The intervertebral disc joint within the spine undergoes millions of loading cycles during decades of life. The cells embedded within the tissue sense and respond to these mechanical signals, which play a vital role in regulating tissue homeostasis and development. This award focuses on answering fundamental questions regarding the range of mechanical signals the cells experience within the tissue and how those signals are sensed. This study will help understand how changes in solute concentration as the tissue is deformed regulates how cells behave in health and disease. The long-term goal of this work is to better understand the disease process within the spine and inform potential treatments for low back pain. This research will also enhance diversity by engaging students traditionally underrepresented within engineering in inter-disciplinary orthopaedic research at the interface of biology and engineering. Specific initiatives to broaden participation by underrepresented students include establishing partnerships with minority serving institutions, bringing undergraduates into the research lab, and participating in middle school outreach in underserved communities to promote STEM awareness. The specific goal of this project is to evaluate the hypothesis that changes in the dynamics (rate and magnitude) of the osmotic environment and change in the cells sensitivity to osmotic cycles contribute to the progression of disease within the intervertebral disc. The first objective is to utilize micro-osmometer and analytical chemistry techniques to determine the dynamics of osmotic cycles at both macro (i.e., tissue level) and micro- (i.e., within the pericellular matrix) scales and determine how the dynamics change with advancing disease. The second objective is to use microfluidic devices, live-cell calcium imaging and pharmacologic modifiers of ion channel activity to determine how osmotic dynamics influence ion channel signaling. This system will also be used to investigate whether activation of co-receptors, increased in the diseased state, can sensitize cellular calcium signaling in response to osmotic cycles. This project will allow the PI to advance the knowledge base in orthopedics, biomechanics, and mechanobiology and establish his long-term career in musculoskeletal mechanobiology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.