Mechanisms of inherited neurodegenerative diseases

在过去的一个财政年度里，我们的项目取得了重大进展。我们在高质量期刊（Ward et al，Science Translational Medicine，2017）上发表了一篇论文，描述了与GRN突变个体中溶酶体功能障碍相关的新临床和病理表型。描述我们从人类干细胞产生大量神经元的新方法的第二篇手稿最近被接受（Wang & Ward等人，Stem Cell Reports）。 我们已经开发了新的蛋白质组学方法，以确定和定量变化的蛋白质组成的溶酶体和相互作用的溶酶体与其他细胞器和胞质蛋白。在缺乏颗粒蛋白前体的干细胞衍生的神经元中使用这些工具，我们已经鉴定了几种蛋白质网络，其在颗粒蛋白前体缺乏的情况下表现出减少的溶酶体募集。我们正在与Janelia的Jennifer Lippincott-Schwartz博士合作，通过假设驱动的实验来调查这些命中。此外，我们还扩大了我们的研究团队，通过招募一名具有质谱专业知识的博士后研究员来提高我们对干细胞神经元进行尖端蛋白质组学分析的能力。最后，我们正在探索使用我们的干细胞衍生的神经元模型的神经退行性疾病的超高通量药物筛选，以确定新的小分子调节细胞存活和异常表型的可能性，与NCATS。

We have made significant progress during the past fiscal year in our project. We one manuscript in a high quality journal (Ward et al, Science Translational Medicine, 2017) describing new clinical and pathological phenotypes related to lysosomal dysfunction in individuals with GRN mutations. A second manuscript describing our new method to generate large quantities of neurons from human stem cells was recently accepted (Wang & Ward et al, Stem Cell Reports). We have developed new proteomic methods to identify and quantify changes to the protein composition within lysosomes and interactions of lysosomes with other organelles and cytosolic proteins. Using these tools in stem cell derived neurons that lack progranulin, we have identified several networks of proteins that exhibit reduced recruitment to lysosomes in the setting of progranulin deficiency. We are in the process of investigating these hits with hypothesis-driven experiments in collaboration with Dr. Jennifer Lippincott-Schwartz at Janelia. Additionally, we have expanded our research team to enhance our ability to perform cutting-edge proteomic analysis of stem cell neurons by recruiting a post-doctoral fellow with expertise in mass spectrometry. Finally, we are exploring the possibility of using our stem cell derived neuronal models of neurodegenerative diseases for ultra-high throughput drug screens to identify new small molecule regulators of cell survival and abnormal phenotypes, in conjunction with NCATS.