There are no animal models for sporadic forms of amyotrophic lateral sclerosis (ALS) and Parkinson?s disease (PD) that account for over 90% of all patients. As the genetics of these diseases are not understood there are no drug targets to go for either. This proposal aims to use MPS devices to produce some of the first sporadic ALS and PD models of disease. Using patient specific induced pluripotent stem cells from rapidly progressing patients with early onset for maximal chance of seeing phenotypes, we will differentiate the cells into motor neurons or dopamine neurons ? the two major cell types affected in the disease. Using cutting edge electrophysiology techniques and metabalomics combined with RNAseq and proteomic analysis we will establish solid biomarkers that define these two diseases when compared to healthy controls (UG3 phase). We will then develop novel MPS screens using the NCATS library of compounds based on the biomarkers discovered in the UH3 phase (UG3 phase). Together these studies will produce some of the first models of sporadic neurological disease using iPSC technology combined with MPS technology. Cedars-Sinai and the company Emulate have a 2 year relationship that forms the foundation of this proposal and an integrated institutional platform on which to collaborate to achieve the goals of the study.

Public Health Relevance

In a collaboration between the MPS company Emulate Inc. and Cedars-Sinai Medical Center this proposal will establish novel biomarkers for sporadic forms of amyotrophic lateral sclerosis and Parkinson?s Disease using a robust MPS platform and patient specific induced pluripotent stem cell technology (UG3). We will then perform a screen of compounds that can reverse patient specific biomarkers using the NCATs small molecule library (UH3). Results from this study will provide novel models of two devastating neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Project #
5UG3NS105703-03
Application #
9786099
Study Section
Special Emphasis Panel (ZTR1)
Program Officer
Lavaute, Timothy M
Project Start
2017-09-15
Project End
2022-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Sances, Samuel; Ho, Ritchie; Vatine, Gad et al. (2018) Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development. Stem Cell Reports 10:1222-1236