The goal of this research proposal is to use patient derived cells with defined disease genotypes to identify disrupted molecular pathways through large-scale proteomics and network analysis. Human induced pluripotent stem cells (hiPSC) have revolutionized the ability to study human diseases from patients. It is now possible to obtain fibroblasts from patients suffering from a disease and to reprogram the cells to pluripotent stem cells and then differentiate them into a cell type associated with the disease state. This reverses a long standing limitation for the proteomic study of human diseases which has been the ability to use cells directly from patients with the appropriate disease phenotype and genotype. We will use Rett Syndrome (RTT) as a prototype for autism spectrum disorders (ASD). Here, we will combine vertical (mutant and control cell lines) and horizontal genetics (different mutations in MeCP2) to measure proteomic changes in affected forebrain neuronal and glial cells derived through fibroblasts and hiPSCs. We will use network analysis techniques developed in the previous grant period to identify molecular phenotypic differences using protein-protein interaction and protein expression patterns. Our hypothesis is that this approach will identify specific molecular processes disrupted in RTT and altered upon rescue of the RTT neuronal phenotype, which will lead to insights into other ASD.

Public Health Relevance

The goal of this research proposal is to use patient derived cells induced pluripotent stem cells with defined disease genotypes to identify disrupted molecular pathways through large-scale proteomics and network analysis. By using a combination of vertical and horizontal genetics to study how protein networks are affected by perturbations to the genetic programs of these cells, we will determine the biochemical implications of the patient genotypes. This research will drive our understanding of the pathways perturbed by the disease, creating a new focus for therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH100175-03
Application #
9029243
Study Section
Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
Program Officer
Koester, Susan E
Project Start
2013-08-01
Project End
2021-03-31
Budget Start
2016-05-10
Budget End
2017-03-31
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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