Rescuing ⍺-synuclein toxicity through neuron-specific enhancement of autophagy

通过神经元特异性增强自噬来解除α-突触核蛋白毒性

• 批准号: 10664568
• 负责人: Jason Paul Chua
• 金额: $ 20.2万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664568
• 关键词: Acceleration; Address; Adverse effects; Affect; Automobile Driving; Autophagocytosis; Autophagosome; Bioinformatics; Biological Models; Biology; CRISPR interference; CRISPR screen; Cell Death; Cell model; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Cytoplasmic Inclusion; Cytoprotection; Development Plans; Disease; Disease Progression; Disease model; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Fellowship; Genes; Goals; Half-Life; Home; Human; Imaging Techniques; Impairment; Induced pluripotent stem cell derived neurons; Institution; Investigation; Knowledge; Label; Late-Onset Disorder; Learning; Measures; Mentors; Mentorship; Metabolism; Methods; Motor; Movement Disorders; Nerve Degeneration; Neurodegenerative Disorders; Neurology; Neurons; Neurosciences Research; North America; Optics; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Physicians; Physiologic pulse; Population; Positioning Attribute; Predisposing Factor; Principal Investigator; Program Development; Proteins; Publishing; Recycling; Regulation; Research; Research Technics; Residencies; Resources; Scientist; Spinobulbar Muscular Atrophy; Stimulus; Symptoms; Testing; Therapeutic; Tissues; Toxic effect; Training; Transcript; Work; alpha synuclein; career; career development; cell type; design; disability; experience; genome-wide; high throughput screening; induced pluripotent stem cell; innovation; knock-down; mTOR inhibition; meetings; mouse model; mutant; myotubularin; neuron loss; neuronal survival; neuroprotection; novel; nutrient deprivation; prevent; proteostasis; proteotoxicity; skills; symptom management; therapeutic target; therapy design; therapy development; translational neuroscience

Project Summary This proposal outlines a five-year career development program aimed at promoting the principal investigator to research independence as a clinician scientist in basic and translational neuroscience, with specialization in cell type-specific mechanisms that regulate neuronal autophagy and modify proteotoxicity in Parkinson disease (PD). Applicant: The applicant has completed M.D. and Ph.D. degrees, residency training in neurology, and fellowship training in PD and movement disorders. He has previous experience in neuroscience research using cell and mouse models to study autophagy in spinobulbar muscular atrophy. His career development plan is designed to focus his research on PD pathogenesis and advance his knowledge in bioinformatics, CRISPR gene editing and high-throughput screening, and advanced imaging techniques. In so doing, the training plan outlined herein builds upon his prior training to achieve research independence. He will benefit from continual mentor engagement, regular meetings and ongoing collaborations. He will learn additional research techniques through formal coursework, workshops, and national meetings. These training mechanisms will provide the applicant with the scientific and conceptual skillset necessary for an independent career in neurodegenerative research. Research Plan: PD is a progressive neurodegenerative disorder marked by motor and non-motor/multi-systemic symptoms that lead to profound disability. There is no effective disease-modifying therapy currently available. Neurodegeneration in PD relates to toxic aggregation of ⍺-synuclein, and mounting evidence shows that ⍺- synuclein can be degraded through the conserved pathway of autophagy. However, current methods to modulate autophagy fail to confer neuroprotective effects in patients. In recently published work, the applicant identified MTMR5 (myotubularin-related phosphatase 5, encoded by the SBF1 transcript) as a potent neuronal autophagy suppressor in neurons. MTMR5 knockdown enhances the sensitivity of neurons to induction of autophagy, and accelerates the degradation of multiple autophagy substrates, including disease-associated and aggregate- prone proteins. In line with this, this proposal will test the central hypothesis that reducing MTMR5 in neurons augments autophagic clearance of ⍺-synuclein and reduces ⍺-synuclein-related neuronal death. The applicant will use human induced pluripotent stem cells (iPSCs) to determine if manipulating SBF1/MTMR5 enhances ⍺- synuclein turnover via autophagy (Aim 1) and modifies ⍺-synuclein proteotoxicity (Aim 2). He will also employ unbiased, genome-wide CRISPR-based screens to uncover key factors regulating MTMR5 in neurons (Aim 3). Collectively, these studies establish a novel research platform focusing on neuronal autophagy, myotubularin biology, and therapy design in PD and related neurodegenerative disorders.

项目总结