Mechanistic Analysis of Genetic Modifiers in Parkinson's Disease

总结 我认为，结合疾病基因发现方法和深入的后续机制， 功能研究是我研究计划的一个独特方面。我们最近发现的“人类特异性”途径 和表型（与小鼠相比）的中脑DA神经元，使我们把重点放在病人来源的DA神经元 来检测PD相关基因的功能通过采用iPS衍生的神经元、小胶质细胞和 星形胶质细胞，我们将研究细胞自主和非细胞自主途径的相互作用，导致 PD中脑DA能神经元功能障碍。此外，我们还将利用创新技术， 在以前不可能的汇集iPS方法中检查大量的遗传变异。 最后，我们最近发现的溶酶体和线粒体之间的直接接触，已经打开了一个完整的 新的机会，检查间和细胞器内的动力学在神经变性。R35奖 给我时间、自由和稳定，让我更有冒险精神，一如既往地追随最 有趣的生物学对这个领域有很大的影响。

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.