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Principal Investigator: Erik Steven Musiek
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $427,625
Funding agency: National Institute on Aging
Abstract
This proposal leverages a new interdisciplinary collaboration between Drs. Guoyan Zhao and Erik Musiek to
define the transcriptional control of astrocyte identities, reactivities, and their roles in in Alzheimer disease (AD)
and Parkinson disease (PD) pathogenesis. AD and PD are heterogeneous, multifactorial disease that selectively
affects certain regions of the brain. Astrocytes are a major glial cell type in the central nervous system that play
critical roles in neural circuit function and brain homeostasis. Accumulating evidence supports astrocyte as a
major contributor of the neurodegenerative processes in AD and AD Related Dementias (AD/ADRD). In our
recently published work, we identified three evolutionarily conserved astrocyte subpopulations which had unique
marker gene expressions shared by the corresponding populations across multiple brain regions and different
disease conditions. However, astrocytes do exhibit regional differences and transcriptomic changes in disease
conditions linked to amyloid pathology, tauopathy, neuronal death, and neurodegenerative diseases, suggesting
that astrocytes may contribute to regional differences in disease susceptibility. From this work, we have identified
ten candidate TFs that exhibited regional differential expression patterns in human astrocytes whose expressions
were dysregulated in disease conditions. Furthermore, these TFs are either known AD risk genes or have known
functions in regulating cell activation or inflammatory response in cell types other than astrocyte. In this proposal,
we will use our established in vitro and in vivo mouse experimental systems and the cutting-edge technologies
of spatial transcriptomics and scRNA-seq to systematically evaluate each candidate TF in regulating astrocyte
property and AD/PD pathogenesis. In Aim 1, we will perform in vitro experimental investigation of candidate TFs
in regulating astrocyte property and neurodegenerative disease pathogenesis.
We will
manipulate candidate TF
expression in primary murine astrocyte-enriched cultures
properties of astrocyte with and without TF manipulation,
astrocyte cultures to sustain growth of mouse cortical
and human astrocytes cell line assess the
including morphological changes, the ability of
neurons, cytokine/chemokine expression,
and
and
phagocytosis capability. In
Aim 2 we will perform MERSCOPE spatial transcriptomic analysis to assess region-
specific expression of candidate TFs. In Aim 3 we will perform in vivo gene knock-down and overexpression
analyses to assess the function of candidate TFs in regulating astrocyte reactivity, neurodegenerative disease
pathology, and the impact on other cell types. If funded and successfully implemented this proposal will provide
validated TFs that regulate astrocyte activation and/or AD/PD pathology relevant to human disease pathogenesis.
These TFs are excellent candidate targets for the development of effective AD or PD treatment strategies.
Terms: <AD dementia><AD related dementia><ADRD><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer risk factor><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Alzheimer's disease risk><Alzheimers Dementia><Ammon Horn><Animal Model><Animal Models and Related Studies><Animals><Anterior><Astrocytes><Astrocytus><Astroglia><Autopsy><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Brain><Brain Nervous System><Brain region><CNS Nervous System><Cell Body><Cell Line><CellLine><Cells><Central Nervous System><Cerebellum><Chemotactic Cytokines><Cognitive><Cornu Ammonis><Corpus Striatum><Corpus striatum structure><Data><Degenerative 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dementia><Paralysis Agitans><Parkinson><Parkinson Disease><Parkinson Disease dementia><Parkinson's Dementia><Parkinson's disease with dementia><Pathogenesis><Pathology><Pattern><Phagocytosis><Physiological Homeostasis><Play><Population><Prefrontal Cortex><Prevention><Primary Parkinsonism><Primary Senile Degenerative Dementia><Process><Property><Publishing><Risk-associated variant><Role><SIS cytokines><Single-Nucleus Sequencing><Slice><Strains Cell Lines><Striate Body><Striatum><Substantia Nigra><Substantia nigra structure><System><Tauopathies><Technology><Therapeutic Intervention><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><United States National Institutes of Health><Work><alzheimer risk><amyloid pathology><astrocytic glia><brain tissue><cell type><chemoattractant cytokine><chemokine><cingulate cortex><cultured cell line><cytokine><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><dementia in PD><dementia in Parkinson disease><developmental><differential expression><differentially expressed><entorhinal cortex><gene biomarker><gene expression biomarker><gene function><gene marker><gene signature biomarker><genetic biomarker><global gene expression><global transcription profile><hiPSC><hippocampal><human disease><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><in vivo><induced human pluripotent stem cells><injury response><interdisciplinary collaboration><intervention therapy><knock-down><knockdown><liability to disease><model of animal><mouse model><murine model><necropsy><nerve cell death><nerve cell loss><nerve cement><neural circuit><neural circuitry><neural degeneration><neurocircuitry><neurodegeneration><neurodegenerative><neurodegenerative illness><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuropathologic tau><neuropathological tau><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><overexpression analysis><postmortem><primary degenerative dementia><progenitor cell model><progenitor model><regional difference><response to injury><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><sNuc-Seq><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single nucleus RNA-sequencing><single nucleus seq><single-cell RNA sequencing><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><stem and progenitor cell model><stem cell based model><stem cell derived model><stem cell model><striatal><synaptic circuit><synaptic circuitry><tau associated neurodegeneration><tau associated neurodegenerative process><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neuropathology><tauopathic neurodegenerative disorder><tauopathy><therapeutically effective><transcription factor><transcriptional differences><transcriptome><transcriptomics><transdisciplinary collaboration><treatment strategy>