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Principal Investigator: Rachel Marie Bear
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $48,974
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Astrocytes are the most abundant glial cell in the brain and are essential for neural circuit formation and neuron
function. Astrocytes have an indispensable role in the developing brain, yet our fundamental understanding of
how astrocytes develop trails our knowledge of neuron development. To develop, astrocytes must proliferate at
the proper time, genetically differentiate, and morphologically mature. Astrocyte dysfunction contributes to the
pathology of several neurodevelopmental disorders, yet these mechanisms are poorly understood. Both
neurons and astrocytes possess a primary cilium, a slender microtubule projection, that serves as a
specialized signaling center for the cell. Cilia are critical regulators of neuron development. However, despite
astrocytes having a primary cilium, the function of astrocyte cilia remains unknown. Disruptions to cilia result in
a class of disorders termed ciliopathies that often result in a spectrum of neurological abnormalities. We must
establish a fundamental understanding of astrocyte cilia because it is likely that they contribute to such
neurodevelopmental diseases. The goal of my research is to create foundational knowledge of the roles that
cilia play in astrocyte development. My preliminary data indicate that astrocyte cilia are necessary for several
stages of astrocyte development. Loss of astrocyte cilia results in altered proliferation, abnormal cellular
morphology, and disrupted expression of developmental astrocyte genes. Therefore, I hypothesize that
astrocyte cilia are critical to regulate astrocyte proliferation and differentiation. This project aims to 1) determine
how cilia regulate astrocyte proliferation and 2) define the role of cilia in astrocyte differentiation. I will use
mouse models to genetically ablate cilia at distinct timepoints, specifically in astrocytes, to investigate the
requirements of cilia at different stages of astrocyte development. I will determine whether cilia regulate the
timing and rate of astrocyte proliferation. Then, to further define how cilia regulate proliferation, I will monitor
cell cycle progression. Next, I will define whether cilia are required for astrocyte differentiation by conducting a
morphological analysis of astrocyte size, spacing, and branching features. Finally, I will conduct a
transcriptomics analysis to determine whether cilia regulate the genetic program of developing astrocytes. I will
also examine astrocyte transcriptional expression at the cellular level to define whether cilia impact
differentiation in specific populations of cortical astrocytes. The proposed experiments will reveal novel
functions of astrocyte cilia and establish a foundation for the roles of ciliary signaling in astrocyte development.
This work will increase fundamental knowledge about astrocyte cilia and how astrocytes develop to improve
our understanding of astrocyte contribution to neurodevelopmental diseases.
Terms: <Ablation><Abscission><Affect><Astrocytes><Astrocytus><Astroglia><Biology><Brain><Brain Nervous System><Cell Body><Cell Communication and Signaling><Cell Cycle><Cell Cycle Progression><Cell Division Cycle><Cell Signaling><Cells><Cellular Morphology><Cilia><Cues><Data><Development><Developmental Gene><Disease><Disorder><Disparate><Dysfunction><Encephalon><Essential Genes><Excision><Extirpation><FISH Technic><FISH Technique><FISH analysis><FISH assay><Fluorescence In Situ Hybridization><Fluorescent in Situ Hybridization><Foundations><Functional disorder><Gene Transcription><General Population><General Public><Genes><Genetic><Genetic Transcription><Glia><Glial Cells><Goals><Hand><Individual><Intracellular Communication and Signaling><Knowledge><Kolliker's reticulum><Label><Link><Mammalian Cell><Mentorship><Micro-tubule><Microtubules><Monitor><Morphology><Nerve Cells><Nerve Unit><Neural Cell><Neural Development><Neurocyte><Neurodevelopmental Disorder><Neuroglia><Neuroglial Cells><Neurologic><Neurological><Neurological Development Disorder><Neurons><Non-neuronal cell><Nonneuronal cell><Pathology><Physiopathology><Play><Population><Position><Positioning Attribute><Proliferating><RNA Expression><Removal><Research><Research Design><Role><Signal Transduction><Signal Transduction Systems><Signaling><Staining method><Stains><Structure><Study Type><Surgical Removal><Synapses><Synaptic><System><Time><Transcript><Transcription><Work><astrocytic glia><biological signal transduction><cell morphology><cell type><ciliopathy><developmental><experiment><experimental research><experimental study><experiments><hands><improved><in vivo><mRNA Expression><mouse model><murine model><nerve cement><neural circuit><neural circuitry><neurocircuitry><neurodevelopment><neurodevelopmental disease><neuron development><neuronal><neuronal development><novel><pathophysiology><programs><resection><social role><study design><synapse><synaptic circuit><synaptic circuitry><tool><transcriptomics>