Neuropsychiatric diseases like schizophrenia and autism have debilitating consequences to individuals and skyrocketing costs of care, creating a great burden to patients and society. The current state of treatment remains plagued by poor outcomes. Genetically mediated abnormalities in the development and architecture of the cerebral cortex play an important role in these diseases. Human neural progenitor cells can be used to model aspects of cortical development in a dish, permitting high-throughput study of disease-associated phenotypes. Here, we will study the genetic underpinnings of two key features of human cortical development: (1) longitudinal changes in gene expression, and (2) neuronal morphology and synaptogenesis. Utilizing the inherent genetic variation observed in neural progenitors from approximately 150 donor lines, we will conduct longitudinal genome-wide association studies to identify the specific genetic variants governing quantitative aspects of human cortical development. This will constitute the first systematic identification of genetic loci influencing cellular neurodevelopmental phenotypes in human cells. We will bridge the gap between genetic variants, molecular and cellular biology, and disease states using model systems of cortical development. Once neurodevelopmental quantitative trait loci are identified, we will then search for a mechanism by which genetic variation causes phenotypic change using recently available genomic engineering techniques. Employing bioinformatics and molecular cloning, we will introduce mutations which have a demonstrated effect on cortical development into the genome of human neural progenitor cells. Cell specific models of disease- related processes will open the door for the discovery, development, and rapid screening of therapeutics. To accomplish the proposed research plan, I will pursue two years of intensive training in neurodevelopmental biology, genetics, and bioinformatics under the supervision and guidance of my mentors. Daniel Geschwind, MD, PhD, my primary mentor and an expert in neurodevelopmental biology and genetics, along with Eleazar Eskin, PhD, my co-mentor and an expert in bioinformatics and statistical genetics, will instruct me in the skills necessary to successfully complete this project. Using the high-throughput sequencing, high content screening, and computational cluster resources found at UCLA, I will be able to efficiently complete these studies with the most current technology available. With the skills learned from this project, I will transition to academic faculty as an independent investigator, pursuing translational research in neuropsychiatric disorders.
Neuropsychiatric diseases such as schizophrenia and autism have debilitating consequences to individuals and skyrocketing costs of care, creating a great burden to patients and society. Genetically mediated abnormalities in the development and architecture of the cerebral cortex play an important role in these diseases. Here, I seek to identify new genetic pathways that create risk for these disorders by finding and validating genetic variants associated with changes in human cortical development in the hopes that they may lead to a better understanding and treatment of these devastating disorders.
| de la Torre-Ubieta, Luis; Stein, Jason L; Won, Hyejung et al. (2018) The Dynamic Landscape of Open Chromatin during Human Cortical Neurogenesis. Cell 172:289-304.e18 |
| Hibar, Derrek P (see original citation for additional authors) (2017) Novel genetic loci associated with hippocampal volume. Nat Commun 8:13624 |
| Adams, Hieab H H (see original citation for additional authors) (2016) Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nat Neurosci 19:1569-1582 |
| Won, Hyejung; de la Torre-Ubieta, Luis; Stein, Jason L et al. (2016) Chromosome conformation elucidates regulatory relationships in developing human brain. Nature 538:523-527 |
| Franke, Barbara; Stein, Jason L; Ripke, Stephan et al. (2016) Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci 19:420-431 |
| de la Torre-Ubieta, Luis; Won, Hyejung; Stein, Jason L et al. (2016) Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22:345-61 |
