We have made significant progress during the past fiscal year in our project. We have published several manuscripts during this time describing new and efficient ways of differentiating human iPSCs into neurons (Fernandopulle et al, Current Protocols in Cell Biology, 2018), and contributed to additional projects as co-authors (She et al, Nature Medicine 2018; Willsey et al, Cell, 2018). Our team also published a co-first author report during the past year (Ward ME et al, Annals of Neurology, 2018). We have continued to refine 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. 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.
|Fernandopulle, Michael S; Prestil, Ryan; Grunseich, Christopher et al. (2018) Transcription Factor-Mediated Differentiation of Human iPSCs into Neurons. Curr Protoc Cell Biol 79:e51|
|Ward, Michael E; Gelfand, Jeffrey M; Lui, Li-Yung et al. (2018) Reduced contrast sensitivity among older women is associated with increased risk of cognitive impairment. Ann Neurol 83:730-738|
|Ward, Michael E; Chen, Robert; Huang, Hsin-Yi et al. (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9:|
|Wang, Chao; Ward, Michael E; Chen, Robert et al. (2017) Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. Stem Cell Reports 9:1221-1233|
|Krencik, Robert; Seo, Kyounghee; van Asperen, Jessy V et al. (2017) Systematic Three-Dimensional Coculture Rapidly Recapitulates Interactions between Human Neurons and Astrocytes. Stem Cell Reports 9:1745-1753|