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Principal Investigator: ARNOLD KRIEGSTEIN
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $1,039,070
Funding agency: National Institute of Neurological Disorders and Stroke
A major long-term goal of this proposal is to understand human brain development and the origins of neurodevelopmental diseases. The cerebral cortex is a structure where model systems, such as mouse or rat, may not capture the complexity of architecture and function relevant for understanding human development and disease. This proposal aims to address the gap in our understanding of human cortical development through the study of primary tissue complemented by human stem cell-derived in vitro model systems, using “cerebral organoids”. Understanding human-specific aspects of brain development is not only critically important for understanding the etiology of neurodevelopmental disorders, including autism and schizophrenia and ultimately developing therapies, but will also benefit our understanding of human cortical evolution, the diversity and lineage of neural cell types, and the mechanisms of cortical expansion - it will help define what makes us unique. The developing human brain contains an enlarged proliferative region, the outer subventricular zone (OSVZ) that is not present in rodents. This study will target two recently discovered neural progenitor cell types found in the OSVZ, outer radial glia (oRG) and intermediate progenitor (IP) cells. These cell types are particularly important as they underlie the huge developmental and evolutionary expansion of the human brain. This proposal seeks to illuminate the complexity of human cortical development in terms of the genomic, cellular, and behavioral features of its constituent oRG and IP neural progenitor cells and their progeny through the key stages of neurogenesis. We plan to discover lineage trajectories that define progenitor-progeny relationships and determine the cellular fates of clonal descendants. We will use novel oRG and IPC markers to enrich progenitor cell populations for analysis, explore the intracellular signaling networks that regulate IP cell expansion, investigate the role of distinct neurogenic niches in creating neuronal diversity, and examine neuron to progenitor signaling pathways that may regulate IPC neurogenesis. Additionally, we will explore the role of oRGs and IPCs in lissencephaly and related neurodevelopmental diseases, and pursue an intriguing relationship between oRG cells and invasive glioblastoma. These ambitious goals are attainable due to recent technological advances, including improvements in single cell genomics, bioinformatics, real time imaging of primary tissue samples, and in vitro models of human cortical development. The outcome holds promise to transform our understanding of human brain development in health and disease.
Terms: <ASD><Address><Architecture><Autism><Autistic Disorder><Behavioral><Bio-Informatics><Bioinformatics><Biologic Models><Biological Models><Body Tissues><Brain><Brain Diseases><Brain Disorders><Brain Nervous System><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cerebral cortex><Cerebrum><Common Rat Strains><Development><Disease><Disorder><Early Infantile Autism><Encephalon><Encephalon Diseases><Engineering / Architecture><Etiology><Evolution><Genomics><Glia><Glial Cells><Glioblastoma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Health><Human><Human Development><Infantile Autism><Intracellular Communication and Signaling><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Kanner's Syndrome><Kolliker's reticulum><Mice><Mice Mammals><Model System><Modern Man><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neural Stem Cell><Neurocyte><Neurodevelopmental Disorder><Neuroglia><Neuroglial Cells><Neurological Development Disorder><Neurons><Non-neuronal cell><Nonneuronal cell><Organoids><Outcome><Population Analysis><Progenitor Cells><Radial><Radius><Rat><Rats Mammals><Rattus><Rodent><Rodentia><Rodents Mammals><Role><Schizophrenia><Schizophrenic Disorders><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Study Subject><Technology><Therapeutic><Tissue Sample><Tissues><agyria><autism spectral disorder><autism spectrum disorder><autistic spectrum disorder><biological signal transduction><causation><cell type><cerebral><dementia praecox><develop therapy><developmental><disease causation><glioblastoma multiforme><human disease><human model><human progenitor cell derived><human stem cell-derived><improved><in vitro Model><intervention development><lissencephaly><lissencephaly pachygyria><malformation><model of human><nerve cement><nerve stem cell><neural><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurodevelopmental disease><neurogenesis><neuron progenitors><neuronal><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><novel><progenitor><progenitor cell expansion><progenitor cell population><progenitor expansion><progenitor population><real-time images><realtime image><schizophrenic><single cell genomics><social role><spongioblastoma multiforme><stem><stem and progenitor cell expansion><stem and progenitor cell population><stem cell expansion><stem cell population><stem cells><subventricular zone><therapy development><treatment development>