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; Won, Hyejung; Stein, Jason L et al. (2016) Advancing the understanding of autism disease mechanisms through genetics. Nat Med 22:345-61|
|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|
|Chiocchetti, A G; Haslinger, D; Stein, J L et al. (2016) Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders. Transl Psychiatry 6:e864|
|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 19:420-31|
|Martinez, Refugio A; Stein, Jason L; Krostag, Anne-Rachel F et al. (2015) Genome engineering of isogenic human ES cells to model autism disorders. Nucleic Acids Res 43:e65|
|Berg, Jamee M; Lee, Changhoon; Chen, Leslie et al. (2015) JAKMIP1, a Novel Regulator of Neuronal Translation, Modulates Synaptic Function and Autistic-like Behaviors in Mouse. Neuron 88:1173-91|
|Hibar, Derrek P; Stein, Jason L; Jahanshad, Neda et al. (2015) Genome-wide interaction analysis reveals replicated epistatic effects on brain structure. Neurobiol Aging 36 Suppl 1:S151-8|
|Ashbrook, David G; Williams, Robert W; Lu, Lu et al. (2014) Joint genetic analysis of hippocampal size in mouse and human identifies a novel gene linked to neurodegenerative disease. BMC Genomics 15:850|
|Stein, Jason L; de la Torre-Ubieta, Luis; Tian, Yuan et al. (2014) A quantitative framework to evaluate modeling of cortical development by neural stem cells. Neuron 83:69-86|