Modeling genetic risk for schizophrenia in human-derived neurons
2025 Award: $60,000
Over 75% of the risk for developing schizophrenia is determined by the genes one inherits. In this project, the Mealer and Heinzen Labs plan to leverage recent advances in genetic studies of schizophrenia and neurons generated from human stem cells to better understand changes in brain development and function that could one day be used design better treatments for severe mental illness.
Need/Problem: Antipsychotic medications, which are used to treat many different psychiatric conditions including schizophrenia, were not developed based on our knowledge of what is changed in the brain or how these disorders are inherited. As such, these treatments commonly provide limited symptom relief and do not appear to alter disease course or offer a chance at cure. Thus, there is incredible opportunity and need for rationally designed treatments based on our understanding of genetic risk and associated brain changes for psychiatric disorders.
Grant Summary: We will CRISPRa and CRISPRi to regulate expression of schizophrenia risk genes in human-induced pluripotent stem cell-derived neurons, to determine how these genes affect neuronal development and function.
Goals & Projected Outcomes: This project has the potential impact of identifying convergent mechanism that contribute to the development of schizophrenia and will provide a new system to test candidate pathways for drug discovery. It will also generate important preliminary data which will be the foundation for a future R01 grant application by Dr. Mealer and foster a new collaboration between Dr. Mealer (PI: Psychiatry/Genetics) and Dr. Heinzen (Co-PI, Pharmacy/Genetics).
Grant Details: In this project, we will study how genetic associations between schizophrenia risk and protein glycosylation affect development and function of human neurons. To accomplish this goal, we will generate human neurons from stem cells in which we can control the level of expression of genes that affect schizophrenia risk using CRISPR activation and CRISPR inhibition. Second, we will determine the functional consequences of perturbing the expression of SCZ risk genes on neurons during development using multiple complementary techniques including electrophysiology, fluorescence microscopy, and N-glycosylation analyses.
