Mitochondrial dysfunction due to aberrant mTOR-regulated mitophagy in autism

自闭症患者 mTOR 调节的线粒体自噬异常导致线粒体功能障碍

基本信息

批准号：
8657109
负责人：
Guomei Tang
金额：
$ 18.36万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-03 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657109
关键词：
Academic Medical Centers Address Affect Alzheimer&apos s Disease Applications Grants Autistic Disorder Autophagocytosis Autopsy Award Axon Behavior Behavioral Biochemical Biochemistry Biology Brain Catabolic Process Cellular biology Child Communication Data Defect Dendrites Dendritic Spines Development Developmental Disabilities Disease Disease model Drug abuse Educational workshop Electron Microscopy Embryo Environment Exhibits Fibroblasts Functional disorder Genetic Goals Grant Health Histological Techniques Human Hyperactive behavior Imaging Techniques Immunohistochemistry Impairment In Vitro Intervention Knowledge Lead Life Light Mediating Mediator of activation protein Membrane Membrane Potentials Mental Depression Mentored Research Scientist Development Award Mentors Mitochondria Mitochondrial Proteins Molecular Molecular Biology Mus Neurodevelopmental Disorder Neurons Neurosciences Neurosciences Research Organelles Oxidative Stress Pathogenesis Pathology Patients Phosphotransferases Postdoctoral Fellow Prevention strategy Proteins Psychiatry Reading Recruitment Activity Reporting Research Research Personnel Role Schizophrenia Scientist Senior Scientist Signal Pathway Signal Transduction Sirolimus Slice Social Interaction Synapses Therapeutic Intervention Ubiquitination United States Vertebral column Western Blotting Work Writing analog autism spectrum disorder career development cellular imaging density design effective intervention experience human FRAP1 protein in vivo insight interdisciplinary approach lymphoblast mitochondrial autophagy mitochondrial dysfunction mitochondrial membrane mouse model neuronal cell body neuropathology neuropsychiatry neurotransmission research study responsible research conduct skills social communication therapy design treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award (K01) is designed to characterize the molecular mechanism underlying mitochondrial dysfunction in autism, with the eventual goal of identifying therapeutic interventions for mitochondrial defects. The applicant (Dr. Guomei Tang) is an Associate Research Scientist at Columbia University Medical Center (CUMC), where internationally renowned basic neuroscience research in psychiatry has been ongoing for many years. CUMC provides a rich environment that supports and encourages Dr. Tang's development and this K01 award will be instrumental for her successful transition to an independent research investigator. Dr. Tang has recruited an outstanding team of mentors, co-mentors, consultants and collaborators with extensive experience in mitochondrial biology and diseases, neuropathology, psychiatry neuropathology, neuroscience, molecular and cell biology, and mTOR-autophagy signaling. These experts will provide her with critical guidance and advice, and enhance her technical and scientific skills for the proposed research. The career development activities include tutorials, directed readings, course work, workshops for mitochondrial biology, skills in collaborating with clinicians and senior scientists, grant writing and presentations, and responsible conduct of research. Dr. Tang's long term research goal is to elucidate the molecular and cellular mechanisms underlying synaptic pathology in autism, and to provide insights into the pathogenesis and potential treatment for autism. To accomplish this, Dr. Tang will use a multidisciplinary approach combining biochemical, histological and imaging techniques to examine mitochondrial autophagy in postmortem autistic brain and mouse models. Her preliminary evidence indicates an association between mitochondrial defects and a dysregulation of mTOR-autophagy signaling in autistic brain. In mouse embryonic fibroblasts (MEFs) and neuronal cultures, mTOR hyperactivation inhibits autophagy, decreases mitochondrial membrane potential and causes an accumulation of damaged mitochondria. These results suggest that mitochondrial dysfunction in autism may result from aberrant mTOR- mediated mitophagy signaling. To address this hypothesis, Dr. Tang proposes 3 specific aims: 1) To determine whether mTOR hyperregulation inhibits neuronal mitophagy and causes mitochondrial dysfunction in ASD mouse models; 2) To examine whether enhancing mitophagy rescues mitochondrial dysfunction in ASD mouse models; and 3) To confirm mitophagy defects in ASD postmortem brain and lymphoblasts. These data will be important for understanding the mechanism by which mTOR kinase regulates mitophagy, elucidating the mitochondrial pathophysiology that underlies ASD pathogenesis, and ultimately to design interventions effective in treatment. The knowledge and experience gained from this proposal will lead directly to a study of the effects of mitophagy defects and mitochondria dysfunction on synaptic pathology in autism, which will be proposed in an R01 grant application in 3-4 years of the award.

描述（由申请人提供）：该指导研究科学家发展奖（K01）旨在描述自闭症线粒体功能障碍的分子机制，最终目标是确定线粒体缺陷的治疗干预措施。申请人（唐国美博士）是哥伦比亚大学医学中心（CUMC）的副研究科学家，该中心多年来一直在进行国际知名的精神病学基础神经科学研究。 CUMC 提供了丰富的环境来支持和鼓励唐博士的发展，此次 K01 奖项将有助于她成功转型为独立研究人员。唐博士招募了一支由导师、共同导师、顾问和合作者组成的优秀团队，他们在线粒体生物学和疾病、神经病理学、精神病学神经病理学、神经科学、分子和细胞生物学以及 mTOR-自噬信号传导方面拥有丰富的经验。这些专家将为她提供重要的指导和建议，并提高她拟议研究的技术和科学技能。职业发展活动包括教程、定向阅读、课程作业、线粒体生物学研讨会、与临床医生和资深科学家合作的技能、资助写作和演示以及负责任的研究行为。唐博士的长期研究目标是阐明自闭症突触病理学的分子和细胞机制，并为自闭症的发病机制和潜在治疗提供见解。为了实现这一目标，唐博士将采用结合生化、组织学和成像技术的多学科方法来检查死后自闭症大脑和小鼠模型中的线粒体自噬。她的初步证据表明线粒体缺陷与自闭症大脑中 mTOR 自噬信号失调之间存在关联。在小鼠胚胎成纤维细胞 (MEF) 和神经元培养物中，mTOR 过度激活会抑制自噬、降低线粒体膜电位并导致受损线粒体积累。这些结果表明，自闭症患者的线粒体功能障碍可能是由 mTOR 介导的线粒体自噬信号传导异常引起的。为了解决这一假设，Tang 博士提出了 3 个具体目标：1）确定 mTOR 过度调节是否会抑制 ASD 小鼠模型中的神经元线粒体自噬并导致线粒体功能障碍； 2) 研究增强线粒体自噬是否可以挽救 ASD 小鼠模型中的线粒体功能障碍； 3) 确认 ASD 死后大脑和淋巴母细胞中的线粒体自噬缺陷。这些数据对于了解 mTOR 激酶调节线粒体自噬的机制、阐明 ASD 发病机制的线粒体病理生理学以及最终设计有效的治疗干预措施非常重要。从该提案中获得的知识和经验将直接导致研究线粒体自噬缺陷和线粒体功能障碍对自闭症突触病理学的影响，该研究将在获奖后 3-4 年的 R01 拨款申请中提出。