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

通过 PI4K2A 介导的溶酶体质量控制拮抗阿尔茨海默病中 tau 蛋白的扩散

• 批准号: 10348532
• 负责人: Xiaojun Tan
• 金额: $ 12.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10348532
• 关键词: 1-Phosphatidylinositol 4-Kinase; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Applications Grants; Astrocytes; Automobile Driving; Autophagocytosis; Award; Biological Assay; Brain; Breeding; CRISPR/Cas technology; Calcium; Categories; Cell model; Cells; Cellular Stress Response; Clinical; Collaborations; Cytosol; Data; Dextran Sulfate; Disease; Disease Progression; Educational process of instructing; Ensure; Event; Exhibits; Extravasation; Functional disorder; Future; Generations; Goals; Grant; Hippocampus (Brain); Human; Impairment; In Vitro; Institutes; International; Invaded; Knockout Mice; Knowledge; Leadership; Learning; Lipids; Lysosomes; Mediating; Membrane; Mentored Research Scientist Development Award; Mentors; Mentorship; Molecular; Mus; Natural Immunity; Nature; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Phosphotransferases; Physiological; Proteins; Quality Control; Research; Research Assistant; Research Personnel; Research Project Grants; Research Training; Role; Seeds; Signal Pathway; Signal Transduction; Site; Symptoms; Tauopathies; Text; Therapeutic; Time; Tissues; Training; Translational Research; Universities; Work; Writing; abeta accumulation; age related; base; career; career development; cell type; effective therapy; experience; improved; in vivo; lipid transport; lysosome membrane; medical schools; mouse model; neuron loss; novel; phosphatidylinositol 4-phosphate; prevent; prion-like; professor; recruit; repaired; response; skills; symposium; tau Proteins; tau aggregation; translational therapeutics

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.

项目摘要/摘要（文本30行）： 该K01提案来自该大学老龄化研究所的研究助理教授Xiaojun Tan博士 匹兹堡医学院。 Tan博士在与 衰老，包括细胞应激反应，自噬，脂质信号传导和先天免疫。 Tan博士正在追求 在衰老研究中的职业，目的是在三年内建立自己的实验室，研究衰老的核心原则 以及神经变性和开发针对年龄相关疾病的新型翻译疗法，尤其是 神经退行性疾病。 K01奖对于为Tan博士提供受保护的时间以供额外的时间至关重要 神经生物学和体内研究和职业发展的培训，以确保他过渡到 独立老龄化调查员。拟议的研究项目是对新的溶酶体质量控制的研究 神经元Tau扩散和阿尔茨海默氏病（AD）的途径。特别是谭博士发现溶酶体 膜透化/损伤（LMP）触发溶酶体上强烈的脂质信号传导，而溶酶体又介导 快速溶酶体修复。该途径取决于LMP刺激的脂质激酶的溶酶体募集 PI4K2A（磷脂酰肌醇4-激酶2型α）。预计快速溶酶体修复有效抑制 tau原纤维在AD中扩散，因为已知内吞tau纤维可以通过触发来侵入受体细胞的细胞质 LMP。这是假设是PI4K2A感觉到tau纤维诱导的LMP并激活快速溶酶体 维修以防止Tau原纤维通过阻塞其溶酶体逃生。将追求两个目标：（1）调查 PI4K2A通过内部tau原纤维感受神经元溶酶体损伤的机制； （2）确定 使用PI4K2A脑特异性的PI4K2A途径对tau扩散和tauopathy的体外和体内影响 淘汰老鼠。为了完成拟议的研究，Tan博士将执行全面的培训计划 包括正式的课程工作，半手，会议和动手培训以及三个的精神训练 与托伦·芬克尔（Toren Finkel）博士成为主要精神和斯泰西·里佐（Stacey Rizzo）和安娜（Ana）博士的领先专家 玛丽亚·库尔沃（Maria Cuervo）担任联合官员。 Finkel博士在开发新的鼠标模型方面具有丰富的经验。 Rizzo博士 是阿尔茨海默氏病和翻译研究的专家。 Cuervo博士是一位国际领导者研究 衰老和神经退行性的细胞质量控制，他还将就Tan博士的职业提供建议 开发和赠款申请。拟议的研究培训将集中于三类（1） 关于神经科学和阿尔茨海默氏病的知识； （2）组织隔离和原发性培养； （3）鼠标模型 产生和表型。奖励期间的职业发展目标包括（1）扩大博士。 Tan的协作网络（2）建立领导力和实验室管理技能，（3）有关 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进步所必需的知识和经验 Tan博士的职业目标是成为研究神经元衰老和AD的独立老龄化研究者。