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

基本信息

批准号：
10551261
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
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10551261
关键词：
1-Phosphatidylinositol 4-Kinase Aging Alzheimer&apos s Disease Amyloid beta-Protein Applications Grants Astrocytes Automobile Driving Autophagocytosis Award Biological Assay Brain Breeding CRISPR/Cas technology Calcium Categories Cell Membrane Permeability Cell model Cells Cellular Stress Clinical Coculture Techniques Collaborations Cytosol Data Dextran Sulfate Disease Disease Progression Educational process of instructing Ensure Event Exhibits Extravasation Functional disorder Future Generations Goals Grant Hippocampus Human Impairment In Vitro International Invaded Knockout Mice Knowledge Leadership Learning Lipids Lysosomes Mediating Membrane Mentored Research Scientist Development Award Mentors Mentorship Microglia Molecular Mus Natural Immunity Nature Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurons Neurosciences Pathogenesis Pathway interactions Patients Phenotype Phosphotransferases Physiological Quality Control Research Research Assistant Research Personnel Research Project Grants Research Training Role Signal Pathway Signal Transduction Site Symptoms Tauopathies Text Therapeutic Time Tissues Training Translational Research Universities Work Writing abeta accumulation age related career career development cell type effective therapy experience improved in vivo lipid transport lysosome membrane medical schools mouse model neuron loss neuroprotection novel pharmacologic phosphatidylinositol 4-phosphate prevent prion-like professor protein aggregation recruit repaired response skills symposium tau Proteins tau aggregation translational therapeutics

项目摘要

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（30 行文本）：这个K01提案来自大学老龄研究所研究助理教授谭晓军博士匹兹堡医学院的 Tan 博士在体外研究方面拥有丰富而多样的经验。陈博士正在研究衰老，包括细胞应激反应、自噬、脂质信号传导和先天免疫。致力于衰老研究，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以及开发针对年龄相关疾病的新型转化疗法，特别是 K01 奖对于为 Tan 博士提供额外的保护时间至关重要。神经生物学和体内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研究者。拟议的研究项目是研究一种新的溶酶体质量控制。具体来说，Tan 博士发现了溶酶体在神经元 tau 扩散和阿尔茨海默病 (AD) 中的作用。膜透化/损伤 (LMP) 触发溶酶体上强大的脂质信号传导，进而介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。 PI4K2A（磷脂酰肌醇4激酶2型α）有望有效抑制快速溶酶体修复。 tau 原纤维在 AD 中扩散，因为已知内吞的 tau 原纤维会通过触发侵入受体细胞的细胞质因此，假设 PI4K2A 感知 tau 原纤维诱导的 LMP 并激活快速溶酶体。通过阻止其溶酶体逃逸来修复 tau 原纤维扩散，我们将追求两个目标：（1）研究。 PI4K2A 通过内化 tau 原纤维感知神经元溶酶体损伤的机制 (2) 确定；使用 Pi4k2a 脑特异性研究 PI4K2A 通路对 tau 扩散和 tau 病的体外和体内影响为了完成拟议的研究，谭博士将实施一项全面的训练计划。包括正式课程、研讨会、会议和实践培训以及来自三位的指导衰老研究领域的顶尖专家，以 Toren Finkel 博士为主要导师，以及 Stacey Rizzo 博士和 Ana 博士作为共同导师的 Maria Cuervo 博士在开发新小鼠模型方面拥有丰富的经验。 Cuervo 博士是阿尔茨海默病和转化研究领域的国际领先研究专家。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拟议的研究培训将集中于三个类别（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；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) 进一步了解指导和教学，以及（4）提高拨款写作和演示技巧。拟议的研究和培训计划将提供必要的知识和经验，以实现谭博士的职业目标是成为一名研究神经衰老和 AD 的独立衰老研究者。