Mitochondrial dysfunction due to aberrant mTOR-regulated mitophagy in autism

描述(由申请人提供)：这个有指导的研究科学家发展奖(K01)旨在描述自闭症患者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。申请者(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提供了一个丰富的环境，支持和鼓励唐博士的发展，而K01奖项将有助于她成功地过渡到一名独立的研究调查员。唐博士招募了一支优秀的导师、合作导师、顾问和合作者团队，他们在线粒体生物学和疾病、神经病理学、精神病学、神经科学、分子和细胞生物学以及mTOR-自噬信号方面拥有丰富的经验。这些专家将为她提供批判性的指导和建议，并为拟议的研究提高她的技术和科学技能。职业发展活动包括教程、定向阅读、课程工作、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、补助金撰写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的分子和细胞机制，并为自闭症的发病机制和潜在的治疗方法提供见解。为了做到这一点，唐博士将使用一种结合了生化、组织学和成像技术的多学科方法，在死后的自闭症大脑和小鼠模型中检查线粒体自噬。她的初步证据表明，自闭症大脑中线粒体缺陷与mTOR自噬信号调节失调之间存在关联。在小鼠胚胎成纤维细胞(MEF)和神经元培养中，mTOR的过度激活抑制了自噬，降低了线粒体膜电位，并导致受损线粒体的积累。这些结果表明，自闭症患者线粒体功能障碍可能是mTOR介导的线粒体吞噬信号异常所致。为了解决这一假设，唐博士提出了三个具体目标：1)确定mTOR过度调控是否抑制ASD小鼠模型中的神经元有丝分裂并导致线粒体功能障碍；2)检查增强有丝分裂是否拯救ASD小鼠模型中的线粒体功能障碍；以及3)确认ASD死后脑和淋巴母细胞中存在有丝分裂缺陷。这些数据将对理解mTOR激酶调节有丝分裂的机制，阐明ASD发病机制下的线粒体病理生理学，以及最终设计有效的治疗干预措施具有重要意义。从这项建议中获得的知识和经验将直接导致一项关于自闭症患者吞丝缺陷和线粒体功能障碍对突触病理的影响的研究，该研究将在该奖项的3-4年的R01拨款申请中提出。

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.