Patient-Derived High-Risk Mutations as a Tool for Deciphering Cellular Parkinson’s Disease-Associated Processes

In this multidisciplinary approach, our ultimate goal is to develop a human-relevant in vitro platform for studying Parkinson's disease (PD), and to use it for identifying PD-associated abnormal pathways using patient-specific differentiated neurovascular niche.

To achieve this ambitious goal, we will pursue the following aims (Figure 1): a) Establish a patient-based human iPSC-derived BBB and neurons (NVU) with LRRK2 and GBA-1 genes mutations as well as dual LRRK2/GBA-1 mutations. b) Identifying the canonical pathways and functional changes caused by the dual mutation by performing systematic measurements of gene expression levels and functional response under common PD mutations. c) Derive predictive models of cellular response to mutations allowing manipulating specific pathways.

The research team consists of an expert in NVU-on-a-Chip and biosensors (Ben Maoz, Bioengineering), an expert in neuroscience and cellular and molecular aspects of Parkinson’s disease (Uri Ashery, Neurobiology) and an expert in computational modeling (Roded Sharan, Computer Science).

The outcome of our integrated ECB framework will be: (i) novel human personalized platform for drug and disease assessment, and (ii) newly identified genomic variations, cellular PD associated phenotypes and disease pathways that can be used to develop novel and specific therapeutic strategies.