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

项目摘要/摘要(30行文本)： 这份K01建议书出自香港大学老龄研究所研究助理教授谭晓军博士之手 匹兹堡医学院的。谭博士在体外研究方面拥有广泛而丰富的经验。 衰老包括细胞应激反应、自噬、脂质信号和先天免疫。谭博士正在进行一项 从事老龄化研究，目标是在三年内建立自己的实验室，研究老龄化的核心原理 和神经退行性变以及为与年龄相关的疾病开发新的翻译疗法，特别是 神经退行性疾病。K01奖在为陈博士提供受保护的时间方面将是至关重要的 在神经生物学和活体研究以及职业发展方面的培训，以确保他过渡到 独立的衰老调查员。本研究课题是一种新型溶酶体质量控制方法的研究。 神经元tau扩散途径与阿尔茨海默病(AD)。具体地说，谭博士发现溶酶体 膜通透性/损伤(LMP)在溶酶体上触发强大的脂质信号，进而介导 快速的溶酶体修复。这一途径依赖于LMP刺激的脂激酶溶酶体募集 PI4K2A(磷脂酰肌醇4-激酶2α)。溶酶体的快速修复有望有效地抑制 在阿尔茨海默病中，tau纤维扩散，因为已知内吞的tau纤维通过触发 LMP。因此，假设PI4K2A感知tau纤维诱导的LMP并激活快速溶酶体 通过阻止其溶酶体逃逸来修复以防止tau原纤维扩散。将追求两个目标：(1)调查 PI4K2A通过内化tau纤维感觉神经元溶酶体损伤的机制；(2)确定 PI4K2a信号通路在体内外对脑特异性tau扩散和tau病的影响 基因敲除老鼠。为了完成拟议的研究，谭博士将实施一项全面的培训计划 包括正式课程工作、研讨会、会议和实践培训，以及来自三个国家的指导 以托伦·芬克尔博士为主要导师，斯泰西·里佐博士和安娜博士为主要导师的老龄化研究领域的领先专家 玛丽亚·库尔沃担任共同导师。芬克尔博士在开发新的老鼠模型方面拥有丰富的经验。里佐博士 是阿尔茨海默氏症和翻译研究的专家。库尔沃博士是一位国际领先的研究人员 在衰老和神经退行性变中的细胞质量控制也将为谭博士的职业生涯提供建议 开发和赠款申请。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 世代和表型。获奖期的职业发展目标包括(1)拓展博士。 Tan的协作网络，(2)建立领导力和实验室管理技能，(3)关于 指导和教学，以及(4)提高赠款的撰写和演示技能。圆满完成 拟议的研究和培训计划将提供取得进展所需的知识和经验 谭博士的职业目标是成为一名研究神经元老化和阿尔茨海默病的独立衰老研究员。

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.