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: 10396113
• 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/10396113
• 关键词: Astrocytes; Award; Biology; Cells; Coculture Techniques; Disease; Freedom; Functional disorder; Genes; Genetic; Human; Lead; 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.

概括 我相信将疾病基因发现方法与深入的后续机制和 功能研究是我的研究计划的一个独特方面，我们最近发现了“人类特异性”途径。 中脑 DA 神经元的表型和表型（与小鼠相比）使我们关注患者来源的 DA 神经元 通过采用 iPS 衍生的神经元、小胶质细胞和细胞的共培养来检查 PD 相关基因的功能。 星形胶质细胞，我们将检查细胞自主通路和非细胞自主通路的相互作用，这些通路导致 此外，我们将使用创新技术同时解决PD中脑DA神经元的功能障碍。 通过汇集 iPS 方法检查大量遗传变异，这在以前是不可能的。 最后，我们最近发现溶酶体和线粒体之间的直接接触完全开启了 R35 奖将为研究神经退行性变的细胞器间和细胞器内动力学提供新的机会。 为我提供时间、自由和稳定，让我更具冒险精神，并一如既往地遵循最 有趣的生物学对该领域产生很大影响。