Mechanistic Analysis of Genetic Modifiers in Parkinson's Disease

摘要 我认为，将疾病基因发现方法与深入的后续机制和 功能研究是我研究项目的一个独特方面。我们最近发现的“人类特有的”通路 中脑DA神经元的表型(与小鼠相比)使我们专注于患者来源的DA神经元 研究PD相关基因的功能。通过采用iPS来源的神经元、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通路之间的相互作用，这些通路导致 帕金森病患者中脑DA神经元功能障碍。此外，我们还将利用创新技术，同时 用综合iPS方法检查大量的遗传变异，这在以前是不可能的。 最后，我们最近发现的溶酶体和线粒体之间的直接接触打开了一个完全 研究神经退行性变的细胞器间和细胞器内动力学的新机会。R35奖将 给我时间、自由和稳定，让我变得更加冒险，并一如既往地遵循最 有趣的生物学对这一领域产生了很大的影响。

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.