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Glial Involvement in REDOX Homeostasis in the Substantia Nigra

胶质细胞参与黑质氧化还原稳态

基本信息

批准号：
10307017
负责人：
Rita Marie Cowell
金额：
$ 66.59万
依托单位：
SOUTHERN RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10307017
关键词：
Acute Age Aging Astrocytes Autopsy Behavior Bioavailable Bioinformatics Brain Cells Cellular Stress Characteristics DNA Repair Data Disease Dopamine Down-Regulation Encephalitis Enzymes Equilibrium Etiology Evaluation Exhibits Extracellular Space Functional disorder Gene Expression Genes Genetic Transcription Genetic Variation Health Homeostasis Human Immune Impairment Infiltration Inflammation Inflammatory Inherited Injections Knockout Mice Laboratories Lewy Bodies Lewy neurites Link Lipopolysaccharides Maintenance Mediator of activation protein Messenger RNA Microglia Mitochondria Modeling Motor Movement Disorders Mus Mutation Neuroglia Neurologic Neurons Niacinamide Nicotinamide adenine dinucleotide Ontology Oxidative Stress Parkinson Disease Pathogenesis Pathway interactions Patients Peripheral Phenotype Process Production Proteins Quantitative Trait Loci Reaction Regulation Research Personnel Role Single Nucleotide Polymorphism Sirtuins Source Substantia nigra structure Synapses Synaptic Vesicles Testing Time Tissues Transcript Work alpha synuclein base carbohydrate metabolism cell type disorder risk dopaminergic neuron experimental study genome wide association study insight mRNA Expression mitochondrial dysfunction mouse model neuron loss neurotransmitter release nicotinamide-beta-riboside novel prevent reconstitution response risk variant synaptic function synucleinopathy trafficking

项目摘要

PROJECT SUMMARY Controversies exist regarding the contribution of glial cell dysregulation and inflammation to the pathogenesis of Parkinson Disease (PD). Signs of inflammation have been detected in postmortem tissue of PD patients, and recent evidence suggests that mutations in genes associated with familial PD can influence the function of astrocytes and microglia. These findings, together with the existence of mutations in the HLA locus in PD patients, have led investigators to propose an etiological role for inflammation and glial dysfunction in PD. However, direct evidence is lacking for mechanistic links among inflammation, glial dysregulation, and the neuronal loss characteristic of PD. To identify potential cell-autonomous mediators of PD-relevant processes in glia, we used a bioinformatics strategy to identify PD GWAS genes enriched in glial cells of the mouse brain. Interestingly, a small subset of genes exhibits enrichment of expression in astrocytes. PD-linked single-nucleotide polymorphisms in one of these genes, CD38, are associated with a ~45% reduction in CD38 transcript expression in the human brain. Previous work has demonstrated a role for CD38 in peripheral immune cells, where it serves to regulate REDOX balance in both intra- and extra-cellular compartments; the roles for CD38 in the brain have only recently been explored. Preliminary experiments from our laboratory have shown that CD38 expression is enriched in astrocytes of the human and mouse brain, NAD/NAM balance is disrupted in various regions of the CD38 knockout mouse brain, and inflammation and CD38 deficiency synergistically interact to influence motor function. Here, we propose to use CD38 as a prototypical gene to understand ways in which glial dysfunction can give rise to a PD-like phenotype in mice by investigating 1) the requirement for CD38 in the maintenance of REDOX homeostasis and dopaminergic neuron function and viability in aging mice, 2) the role for CD38 in the regulation of inflammation in the substantia nigra, and 3) the impact of CD38 modulation on the vulnerability of dopaminergic neurons in two synucleinopathy mouse models of PD. A subset of experiments will test the involvement of REDOX dysregulation in the changes observed in CD38-deficient mice by determining whether provision of nicotinamide riboside, a bioavailable NAD precursor, can prevent dopaminergic oxidative stress, cell dysfunction, and loss. Altogether, these experiments have the potential to reveal mechanistic contributors to increased neuronal vulnerability with glial dysfunction and provide novel information about the roles for glia in maintaining dopaminergic neuron survival in aging and disease.

项目总结