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

确定 Ca2 结合蛋白在毛细胞机械转导调节中的作用

• 批准号: 10437034
• 负责人: Zizhen Wu
• 金额: $ 35.91万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437034
• 关键词: AMPA Receptors; Advisory Committees; Affect; Antibodies; Area; Auditory; Auditory Perception; Binding; Binding Proteins; Biochemistry; Biology; Calcium and Integrin Binding Protein 2; Cell physiology; Co-Immunoprecipitations; Cochlea; Complement; Complex; Defect; Dependence; Development; Disease; Doctor of Philosophy; Electrophysiology (science); Equilibrium; Fellowship; Foundations; Goals; Hair; Hair Cells; Health Sciences; Hearing; Human; Integral Membrane Protein; Interview; Kinetics; Knowledge; Laboratories; Laboratory Research; Labyrinth; Link; Mentors; Molecular; Molecular Biology; Motor; Myosin ATPase; Occupations; PCDH15 gene; Pattern; Phase; Play; Principal Investigator; Process; Property; Proteins; Regulation; Research; Research Institute; Research Personnel; Role; Scientist; Sensory; Sensory Disorders; Signal Transduction; Social Impacts; Solid; Speed; Spinal cord injury; Supervision; Techniques; Testing; Texas; Training; Training Programs; Universities; Vestibular Hair Cells; Vestibule; Work; Yeasts; analog; career development; chronic pain; deafness; economic impact; effective therapy; equilibration disorder; experimental study; hearing impairment; insight; loss of function; mechanical stimulus; mechanotransduction; meetings; mouse model; protein function; public health relevance; yeast two hybrid system

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.

抽象的 首席调查员在休斯敦的德克萨斯大学健康科学中心获得了博士学位 他所做的工作以了解脊髓损伤引起的慢性疼痛的机制 Edgar T. Walters博士的监督。然后，他搬到了La Jolla的Scripps研究所（TSRI） 他加入了乌尔里希·穆勒（Ulrich Mueller）博士的实验室，训练听觉感知 耳蜗毛细胞。最近，他与穆勒博士一起搬到了约翰·霍普金斯大学（JHU），许多顶级 感官生物学的科学家立即可用，他继续他的博士后奖学金 获得分子生物学和小鼠建模的培训。此外，要协助候选人具体 技术，帮助识别就业机会，为他做好工作准备，并帮助他建立一个实验室 咨询团队成立了。该团队包括Drs。 Ulrich Mueller，Elisabeth Glowatzki，Bin Wu和Zhaozhu Qiu，是JHU的调查员，对职业发展和实验室的最新知识 管理。最后，拟议的课程，科学会议和研讨会将补充他的培训 实现他成为成功的独立调查员的目标的计划。 拟议工作的长期研究目标是寻求答案，以解决该领域的挑战性问题 感觉生物学至1）毛细胞中机械转移通道的组成部分，以及2） 负责调节毛细胞机械转导的机制是什么？为了实现这些目标， 他将专门针对两类蛋白质：（i）在酵母双杂交屏幕中鉴定出的蛋白质 与TMHS/LHFPL5相互作用，这是毛细胞机械转导复合物的组成部分； （ii）Ca2+结合 是调节转导的候选者的蛋白质。研究计划提议检验中心假设 与之结合的LHFPL5和蛋白质是毛细胞中较大的机械转导通道复合物的一部分。 一些蛋白质可能会导致通道孔，而另一些蛋白质可能扮演调节角色。 Ca2+ 预测绑定蛋白对于据可记录的转导机械的调节至关重要 到Ca2+。拟议的研究将分析这些蛋白质在两种人工耳蜗中的机械传导中的作用 毛细胞和前庭毛细胞。蛋白质功能将使用结合的实验策略进行测试 电生理学，生物化学和小鼠建模。结果将为支持 首席研究者的研究目标有望提供1）对机械转移的更好理解 毛细胞中的通道，以及2）对通道调节机制（例如适应）的洞察力。