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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Enabling Bioanalytical and Imaging Technologies Study Section (EBIT)
Program Officer
Koester, Susan E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Ma, Yuanhui; Yates 3rd, John R (2018) Proteomics and pulse azidohomoalanine labeling of newly synthesized proteins: what are the potential applications? Expert Rev Proteomics 15:545-554
Yates 3rd, John R (2018) Content Is King: Databases Preserve the Collective Information of Science. J Biomol Tech 29:1-3
Brito, Anita; Russo, Fabiele Baldino; Muotri, Alysson Renato et al. (2018) Autism spectrum disorders and disease modeling using stem cells. Cell Tissue Res 371:153-160
Trujillo, Cleber A; Muotri, Alysson R (2018) Brain Organoids and the Study of Neurodevelopment. Trends Mol Med 24:982-990
Liu, Han-Hsuan; McClatchy, Daniel B; Schiapparelli, Lucio et al. (2018) Role of the visual experience-dependent nascent proteome in neuronal plasticity. Elife 7:
Thomas, Charles A; Tejwani, Leon; Trujillo, Cleber A et al. (2017) Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation. Cell Stem Cell 21:319-331.e8
Ma, Yuanhui; McClatchy, Daniel B; Barkallah, Salim et al. (2017) HILAQ: A Novel Strategy for Newly Synthesized Protein Quantification. J Proteome Res 16:2213-2220
Marchetto, Maria C; Belinson, Haim; Tian, Yuan et al. (2017) Altered proliferation and networks in neural cells derived from idiopathic autistic individuals. Mol Psychiatry 22:820-835
Herai, Roberto H; Negraes, Priscilla D; Muotri, Alysson R (2017) Evidence of nuclei-encoded spliceosome mediating splicing of mitochondrial RNA. Hum Mol Genet 26:2472-2479
Chatterjee, Sandip; Stupp, Gregory S; Park, Sung Kyu Robin et al. (2016) A comprehensive and scalable database search system for metaproteomics. BMC Genomics 17:642

Showing the most recent 10 out of 26 publications