Antagonizing tau spreading in Alzheimer’s disease by PI4K2A-mediated lysosomal quality control

项目总结/摘要（30行文本）： 这份K 01建议书是来自大学老龄研究所的研究助理教授谭晓君博士 匹兹堡医学院Tan博士在体外研究方面具有广泛而多样的经验， 衰老包括细胞应激反应、自噬、脂质信号传导和先天免疫。谭医生正在寻找 从事衰老研究，目标是在三年内建立自己的实验室，研究衰老的核心原理 和神经退行性疾病，并开发新的转化治疗与年龄有关的疾病，特别是 神经退行性疾病K 01奖将是至关重要的，为谭博士提供受保护的时间， 在神经生物学和体内研究以及职业发展的培训，以确保他过渡到一个 独立的老龄化调查员拟议的研究项目是一种新的溶酶体质量控制的研究 神经元tau扩散和阿尔茨海默病（AD）的途径。具体来说，谭博士发现， 膜透化/损伤（LMP）触发溶酶体上的强脂质信号传导， 快速溶酶体修复该途径依赖于LMP刺激的脂质激酶的溶酶体募集 PI 4K 2A（磷脂酰肌醇4-激酶2 α）。快速溶酶体修复有望有效抑制 在AD中扩散的tau原纤维，因为已知内吞的tau原纤维通过触发内吞而侵入受体细胞的胞质溶胶。 进出口股份因此，假设是PI 4K 2A感知由tau纤维诱导的LMP并激活快速溶酶体， 修复以通过阻断其溶酶体逃逸来防止tau纤维扩散。两个目标将被追求：（1）调查 PI 4K 2A通过内化的tau纤维感知神经元溶酶体损伤的机制;（2）确定 使用Pi 4k 2a脑特异性免疫组织化学方法研究PI 4K 2A途径对tau扩散和tau蛋白病的体外和体内影响。 敲除小鼠为了完成这项研究，谭博士将实施一项全面的培训计划 包括正式的课程工作，研讨会，会议和实践培训，以及来自三个 老化研究的领先专家，Toren Finkel博士是主要导师，Stacey Rizzo博士和Ana博士 Maria Cuervo作为共同导师。Finkel博士在开发新的小鼠模型方面具有丰富的经验。里佐医生 是阿尔茨海默病和转化研究的专家。Cuervo博士是一位国际领导人， 衰老和神经退行性疾病的细胞质量控制，他还将为谭博士的职业生涯提供建议 发展和赠款申请。拟议的研究培训将侧重于三个类别（1） 神经科学和阿尔茨海默病知识;（2）组织分离和原代培养;（3）小鼠模型 生成和表型分析。奖励期内的职业发展目标包括（1）扩大博士。 Tan的协作网络，（2）培养领导力和实验室管理技能，（3）额外学习 指导和教学，以及（4）提高赠款写作和演示技巧。成功完成 拟议的研究和培训计划将提供必要的知识和经验， 博士Tan的职业目标是成为一名独立的衰老研究者，研究神经元衰老和AD。

PROJECT SUMMARY/ABSTRACT (30 lines of text): This K01 proposal is from Dr. Xiaojun Tan, Research Assistant Professor in the Aging Institute at the University of Pittsburgh School of Medicine. Dr. Tan has extensive and diverse experience with in vitro studies related to aging including cellular stress response, autophagy, lipid signaling, and innate immunity. Dr. Tan is pursuing a career in aging research with a goal of establishing his own lab in three years studying core principles in aging and neurodegeneration and developing novel translational therapeutics for age-related diseases, especially neurodegenerative diseases. A K01 Award would be critical in providing Dr. Tan with protected time for additional training in neurobiology and in vivo studies as well as career development to ensure his transitioning into an independent aging investigator. The proposed research project is the study of a new lysosomal quality control pathway in neuronal tau spreading and Alzheimer’s disease (AD). Specifically, Dr. Tan discovered that lysosomal membrane permeabilization/damage (LMP) triggers robust lipid signaling on lysosomes which in turn mediates rapid lysosomal repair. This pathway is dependent on LMP-stimulated lysosomal recruitment of the lipid kinase PI4K2A (phosphatidylinositol 4-kinase type 2 alpha). Rapid lysosomal repair is expected to effectively suppress tau fibril spreading in AD, as endocytosed tau fibrils are known to invade the cytosol of recipient cells by triggering LMP. Thus, the hypothesis is that PI4K2A senses LMP induced by tau fibrils and activates rapid lysosomal repair to prevent tau fibril spreading by blocking its lysosomal escape. Two aims will be pursued: (1) investigate the mechanism by which PI4K2A senses neuronal lysosomal damage by internalized tau fibrils; (2) determine the in vitro and in vivo impact of the PI4K2A pathway on tau spreading and tauopathy using Pi4k2a brain-specific knockout mice. To accomplish the proposed research, Dr. Tan will carry out a comprehensive training plan including formal course work, seminars, conferences and hands-on training as well as the mentorship from three leading experts in aging research with Dr. Toren Finkel as the primary mentor and Dr. Stacey Rizzo and Dr. Ana Maria Cuervo as co-mentors. Dr. Finkel has significant experience in developing new mouse models. Dr. Rizzo is an expert of Alzheimer’s disease and translational research. Dr. Cuervo is an international leader studying cellular quality control in aging and neurodegeneration who will also provide advice on Dr. Tan’s career development and grant applications. The proposed research training will focus on three categories (1) knowledge in neuroscience and Alzheimer’s disease; (2) tissue isolation and primary cultures; (3) mouse model generation and phenotyping. The career development goals in the award period include (1) expanding Dr. Tan’s collaboration network, (2) building leadership and lab management skills, (3) additional learning about mentoring and teaching, and (4) improving grant writing and presentation skills. Successful completion of the proposed research and training plan will provide the knowledge and experience necessary to progress toward Dr. Tan’s career goal of becoming an independent aging investigator studying neuronal aging and AD.