Mechanistic Analysis of Genetic Modifiers in Parkinson's Disease

帕金森病基因修饰的机制分析

• 批准号: 10612362
• 负责人: DIMITRI KRAINC
• 金额: $ 120万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612362
• 关键词: Astrocytes; Award; Biology; Cells; Coculture Techniques; Disease; Freedom; Functional disorder; Genes; Genetic; Human; Link; Lysosomes; Microglia; Midbrain structure; Mitochondria; Mus; Nerve Degeneration; Neuroglia; Neurons; Parkinson Disease; Pathway interactions; Patients; Phenotype; Research; Time; dopaminergic neuron; follow-up; gene discovery; genetic analysis; genetic variant; induced pluripotent stem cell; innovative technologies; novel; programs

Summary I believe that combining disease gene discovery approaches with in-depth follow-up mechanistic and functional studies is a unique aspect of my research program. Our recent discovery of “human-specific” pathways and phenotypes (compared to mice) in midbrain DA neurons has led us to focus on patient-derived DA neurons to examine the function of PD-linked genes. By employing co-cultures of iPS-derived neurons, microglia and astrocytes, we will examine the interplay of cell-autonomous and no-cell autonomous pathways that lead to dysfunction of midbrain DA neurons in PD. Moreover, we will use innovative technology to simultaneously examine a large number of genetic variants in a pooled iPS approach that has not been possible previously. Finally, our recent discovery of direct contacts between lysosomes and mitochondrial has opened a completely new opportunity to examine inter- and intra-organellar dynamics in neurodegeneration. The R35 award would provide me the time, freedom and stability to be even more adventurous and, as always, follow the most interesting biology to have a high impact on the field.

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