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Principal Investigator: Mara Burns
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $45,863
Funding agency: National Institute of Neurological Disorders and Stroke
Project Summary / Abstract:
Astrocytes are known to be dysfunctional in Huntington’s disease (HD); however, further research is needed
to understand how these star-like cells develop in the context of HD. HD is a devastating, progressive, genetic
neurodegenerative disease, and recent work suggests mutant Huntingtin (mHTT), the cause of disease, may
trigger early molecular and cellular changes during neurodevelopment that sets up susceptibility. Data suggests
mHTT impacts the maturation of neural cells into adult life and throughout disease progression. While HD is
primarily characterized by the degeneration of medium spiny neurons in the striatum and atrophy of the cortex,
astrocytes have become a prominent cell type of interest as a contributor to the onset and progression of the
disease. Astrocytes guard and support the brain by stabilizing the blood-brain barrier, responding to stressors,
and regulating ions and neurotransmitter homeostasis, all of which are dysregulated in HD. Our lab at UC Irvine
has shown developmental deficits using single-nuclei RNA sequencing (snRNAseq) in HD human induced PSC-
derived astrocytes (iAstros) and in rapidly progressing R6/2 HD mouse cortex and striatum. We also confirmed
that HD iAstros have decreased RNA and protein of transcription factors (TFs) SOX9 and ATF3, results that
support a role for these TFs in dysregulated maturation and developmental pathways. Lacking in the snRNAseq
from mice is spatial information, thus I conducted spatial transcriptomics of postnatal day 0 (P0), 4-week and 12-
week-old control and R6/2 mice and found early dysregulation of astrocytic developmental genes and a possible
role for neuronal-derived signaling factors in astrocyte developmental impairment. Several questions remain: 1)
whether HD astrocyte dysmaturation is an initial delay of maturation or a persistent impairment, 2) what is
mechanistically driving spatial maturation impairments, and 3) what the impact is of astrocyte deficits on
neighboring cells. I hypothesize that early impairments in astrocyte maturation set up susceptibility to HD
progression later in life. To begin to address these gaps in knowledge, in Aim 1, I will investigate the role of
dysregulated TFs, SOX9 and ATF3, with overexpression and knockdown in iAstros and assess cellular
maturation, function, morphology, and transcriptomic pathways. Aim 2 then utilizes the spatial transcriptomics
data integrated with snRNAseq to evaluate temporal and spatial regulators of regional changes with a focus on
astrocyte development and maturation, and the contributions of neuronal-astrocyte signaling. I will infer cellular
communication between neurons and astrocytes through ligand-receptor analysis and functionally validate my
preliminary findings in vitro with iAstros. This proposal uses innovative approaches to provide the scientific
community with a novel investigation of dysfunctional astrocytic developmental trajectories in HD with the aim of
influencing early therapeutic interventions to impact the onset or progression of disease. My laboratory
environment at UCI and individualized mentorship from my sponsors supporting my research skills in perturbing
in vitro cell models and bioinformatics analysis will help to burgeon my growth as a young scientist.
Terms: <21+ years old><ATF-3><ATF3><Address><Adult><Adult Human><Antioxidants><Assay><Astrocytes><Astrocytus><Astroglia><Attention><Automobile Driving><Autoregulation><Back><Basal Ganglia><Basal Nuclei><Basal Transcription Factor><Basal transcription factor genes><Bio-Informatics><Bioassay><Bioinformatics><Biological Assay><Blood - brain barrier anatomy><Blood-Brain Barrier><Body Tissues><Brain><Brain Nervous System><CAG repeat><CAG trinucleotide repeat><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Function><Cell Interaction><Cell Maturation><Cell Nucleus><Cell Physiology><Cell Process><Cell Signaling><Cell model><Cell-to-Cell Interaction><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular model><Cognition><Communication><Communities><Corpus Striatum><Corpus striatum structure><Data><Data Analyses><Data Analysis><Data Set><Degenerative Neurologic Disorders><Dependence><Development><Developmental Gene><Developmental Process><Diathesis><Disease><Disease Progression><Disease susceptibility><Disorder><Dorsum><Down-Regulation><Encephalon><Environment><Exons><GLAST><GLAST Protein><Gene Proteins><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Transcription><Glutamate-Aspartate Transporter><Glutamates><Growth><HD Gene><HD protein><Hemato-Encephalic Barrier><Hereditary><Heterogeneity><Homeostasis><Huntingtin><Huntingtin Protein><Huntington Chorea><Huntington Disease><Huntington gene><Huntington protein><Huntington's><Huntington's Disease><Huntington's disease gene product><Huntingtons Disease><IGF1><IGF1 gene><IGFI><IT15 gene><Impairment><In Vitro><Individual><Inherited><Intracellular Communication and Signaling><Investigation><Ions><Knowledge><L-Glutamate><Laboratories><Life><Ligands><Literature><Maps><Mentorship><Messenger RNA><Mice><Mice Mammals><Molecular><Morphology><Movement><Murine><Mus><Mutate><Nerve Cells><Nerve Degeneration><Nerve Transmitter Substances><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural Development><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurodevelopmental Deficit><Neurologic Degenerative Conditions><Neuron Degeneration><Neurons><Neurotransmitters><Non-Polyadenylated RNA><Nucleus><Outcome Measure><Paint><Pathologic><Pathology><Pathway interactions><Patients><Personal Satisfaction><Personality><Phenotype><Physiological Homeostasis><Poly Q><Predisposition><Probabilistic Models><Probability Models><Process><Protein Gene Products><Proteins><RNA><RNA Expression><RNA Gene Products><Receptor Protein><Regional Disease><Research><Research Resources><Resolution><Resources><Ribonucleic Acid><Role><Scientist><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Statistical Models><Stress><Striate Body><Striatum><Subcellular Process><Survey Instrument><Surveys><Susceptibility><T cell factor 4><T cell transcription factor 4><T-Cell-Specific Transcription Factor 4><TCF-4><TCF4><TCF7L2><TCF7L2 gene><Tcf4 transcription factor><Tcf712 transcription factor><Testing><Therapeutic Intervention><Time><Tissue Growth><Tissues><Transcription><Transcription Factor 7-Like 2><Transcription Factor Proto-Oncogene><Transcription factor genes><Work><activating transcription factor 3><adulthood><astrocytic glia><bio-informatics tool><bioinformatics tool><biological signal transduction><bloodbrain barrier><body movement><brain atrophy><brain cell><cell type><cerebral atrophy><cortical atrophy><data integration><data interpretation><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><driving><driving force><functional improvement><functional outcomes><glutamatergic><human disease><iPS><iPSC><iPSCs><improve function><improved><improved functional outcomes><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><innovate><innovation><innovative><insight><interest><interesting transcript 15><intervention therapy><knock-down><knockdown><liability to disease><mRNA><measurable outcome><mitochondrial metabolism><mouse model><murine model><mutant><neural degeneration><neurodegeneration><neurodegenerative><neurodegenerative illness><neurodevelopment><neurological degeneration><neuronal><neuronal degeneration><neuropathologic><neuropathological><neuropathology><neurotransmitter metabolism><novel><ontogeny><outcome measurement><overexpress><overexpression><pathway><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient-derived pluripotent stem cells><polyQ><polyglutamine><postnatal><receptor><resolutions><response><sNuc-Seq><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><skills><snRNA sequencing><snRNA-seq><social role><spatial integration><statistical linear mixed models><statistical linear models><stressor><striatal><therapeutic target><transcription factor><transcriptomics><translation strategy><translational approach><translational strategy><uptake><well-being><wellbeing>