Neuromuscular Junction Dysfunction in Hyperkalemic Periodic Paralysis - Project Summary / Abstract Career Development Context: This proposal presents a five-year research and career development program focused on advanced, intracellular, electrophysiological training to improve the care of patients with neuromuscular disease. The candidate (Adam Deardorff) is an early career MD/PhD trained clinician-scientist with board certification in neurology and additional fellowship training with board eligibility in neuromuscular medicine. He is junior faculty at the Wright State University Boonshoft School of Medicine with appointments in the Department of Neuroscience, Cell Biology, and Physiology and the Department of Neurology. Under the expert guidance of his primary mentor (Dr. Mark Rich) and scientific advisory committee, the outlined proposal builds upon the candidate’s previous research and clinical expertise by integrating new training in translational neuromuscular physiology with clinically relevant and rapidly translatable hypothesis testing. At the completion of the funding period, he will have the necessary skills to undertake the physiologic analysis of every aspect of the motor unit / segmental motor system, generate his own highly effective research programs, and collaborate with other investigators around the world to advance patient care. The proposed experiments, training activities, and mentorship are therefore vital to his long-term career goal of improving the lives of patients with neuromuscular disease. Research Context: Hyperkalemic Periodic Paralysis (HPP) is a rare genetic disorder due to a mutation affecting muscle sodium channels. Patients experience episodic attacks of paralysis lasting minutes to days when their blood potassium levels increase (by diet or exercise, for example). Afflicted individuals also experience significant long-term sequelae, including progressive muscle weakness, muscle pain, and fatigue. Unfortunately, there are few effective treatments for HPP outside of lifestyle modification. This proposal strongly suggests that a) the primary mechanism of weakness in HPP has been missed and b) it is caused by reversible failure of the neuromuscular junction (NMJ) rather than muscle fiber hypoexcitability (as has been previously thought). Therefore, the experiments in this proposal will for the first time provide a highly detailed and systematic investigation of muscle hypoexcitability (Aim 1) and the novel consideration of NMJ failure (Aim 2) in HPP. Establishing reversible NMJ failure as an important cause of weakness will dramatically advance our mechanistic understanding of HPP disease pathogenesis and suggest novel mechanisms of treatment with therapeutics already FDA-approved to correct NMJ failure in other illnesses. After the K08 grant period, the candidate will submit grant applications to test these novel therapeutic interventions and, if successful, rapidly translate the findings into a clinical trial. Moreover, the findings would suggest NMJ dysfunction may be more common than previously thought and could lead to new therapies in other muscle diseases as well.
