Determining the roles of Ca2+-binding proteins in modulation of hair cell mechanotransduction

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ABSTRACT The principal investigator received his PhD at the University of Texas Health Science Center at Houston for the work he performed to understand the mechanisms underlying spinal cord injury-induced chronic pain under the supervision of Dr. Edgar T. Walters. He then moved to The Scripps Research Institute (TSRI), La Jolla, where he joined Dr. Ulrich Mueller's laboratory to train in auditory perception, specifically in mechanotransduction of cochlear hair cells. Recently, he moved with Dr. Mueller to Johns Hopkins University (JHU), where many top scientists in sensory biology are immediately available and where he continues his postdoctoral fellowship to obtain training in molecular biology and mouse modeling. Furthermore, to assist the candidate with specific techniques, help identify job opportunities, prepare him for job interviews, and help him build a laboratory, an advisory team was formed. This team includes Drs. Ulrich Mueller, Elisabeth Glowatzki, Bin Wu and Zhaozhu Qiu, who are investigators at JHU with the most current knowledge about career development and lab management. Finally, proposed courses, scientific meetings and seminars will complement his training program to accomplish his goal of becoming a successful independent investigator. The long-term research goal of the proposed work is to seek answers to challenging questions in the area of sensory biology as to 1) what are the components of the mechanotransduction channel in hair cells, and 2) what is the mechanism responsible for modulation of hair cell mechanotransduction. To achieve these goals, he will specifically focus on two classes of proteins: (i) proteins identified in a yeast two-hybrid screen that interact with TMHS/LHFPL5, a component of the mechanotransduction complex of hair cells; (ii) Ca2+ binding proteins that are candidates to regulate transduction. The research plan proposes to test the central hypothesis that LHFPL5 and proteins that bind to it are part of a larger mechanotransduction channel complex in hair cells. Some of the proteins might contribute to the channel pore while others might play modulatory roles. Ca2+ bindings proteins are predicted to be critical for the well-documented regulation of the transduction machinery to Ca2+. The proposed studies will analyze the role of these proteins in mechanotransduction in both cochlear hair cells and vestibular hair cells. Protein function will be tested using an experimental strategy that combines electrophysiology, biochemistry, and mouse modeling. The results will provide a solid foundation to support the principal investigator's research goals that promise to offer 1) a better understanding of mechanotransduction channels in hair cells, and 2) insights into the mechanisms of channel regulation such as adaptation.