Mitochondrial dysfunction due to aberrant mTOR-regulated mitophagy in autism

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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.