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The role of PPARγ in astrocyte pathobiology after exposure to repetitive mild traumatic brain injury

PPARγ 在重复性轻度脑外伤后星形胶质细胞病理学中的作用

基本信息

批准号：
10739968
负责人：
Joseph O Ojo
金额：
$ 44.94万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10739968
关键词：
Acute Address Adopted Agonist Alzheimer&apos s disease related dementia Astrocytes Automobile Driving Autopsy Behavioral Biochemical Markers Bioenergetics Blood - brain barrier anatomy Brain Brain Injuries Calcium Cell Survival Cells Cellular Metabolic Process Cerebrovascular Circulation Chronic Cicatrix Clinical Clinical Trials Color Consultations Contracts Data Development Disease Ensure Event Exposure to Flow Cytometry Future Gene Expression Genes Genetic Gliosis Goals Human Image Impairment Inflammation Inflammatory Injury Intervention Investigation Knowledge Learning Ligands Lipid A Mediating Memory Metabolic Metabolism Microglia Modeling Molecular Bank Morphology Nerve Degeneration Nervous System Trauma Neurodegenerative Disorders Neuroglia Neurologic Neurologic Dysfunctions Neurons Outcome Oxidative Stress PPAR gamma Pathogenesis Pathologic Pathology Performance Peroxisome Proliferator-Activated Receptors Phagocytosis Phenotype Play Pre-Clinical Model Property Receptor Activation Recovery Research Design Retrospective Studies Risk Role Sensorimotor functions Signal Transduction Sorting Specificity Suspensions Synapses TBI Patients Tamoxifen Therapeutic Time Tissues United States National Institutes of Health Work astrogliosis axon injury axon regeneration behavioral outcome cell type constitutive expression density differential expression functional outcomes immune function immunoregulation in vivo lipid metabolism mild traumatic brain injury mouse model neurobehavioral neuroinflammation neuroprotection neurotoxic new therapeutic target novel novel therapeutics overexpression pharmacologic pre-clinical prophylactic receptor response single cell analysis tau Proteins therapeutic target timeline transcriptome sequencing transcriptomics translational potential treatment strategy

项目摘要

Repetitive mild traumatic brain injury (r-mTBI) can induce neurological damage many years after the cessation of injury, increasing the risk for ADRD. No disease-modifying treatment strategies have been developed to mitigate the long-term consequences of r-mTBI. There is an urgent need to advance our current understanding of the cellular mechanisms driving the cascade of secondary injury events, as this could lead to the identification and development of novel therapeutics. Astrocytes play an important role in these secondary injury events. After acute insult, they undergo a dramatic transcriptomic and morphological transformation. Reactive astrocytes can be polarized into different states adopting neuroprotective or neurotoxic properties that can influence brain recovery. Neuroprotective astrocytes can serve to create a physical barrier to limit the spread of damage, preventexcitotoxicity, boost metabolic support for neurons, and release trophic factors to promote neurorepair. While neurotoxic astrocytes can take a dual role of neuroinflammation and glial scar formation that inhibits axonal regeneration and promotes neuronal damage, and this can be accompanied by loss of their constitutive supportive roles. Our knowledge of the mechanisms that regulate astrocyte phenotypes and responses in the healthy brain or after brain injury is lacking. To address this, we established a mouse model of r-mTBI that recapitulates many of the features of human TBI and thus represents a translationally relevant preclinical platform. Using this model, we generated a molecular library of astroglia gene profiles, at a range of timepoints post-injury that provides a unique and detailed time-course of the astroglia response to TBI. Particularly, we reveal deficits in cellular metabolism, oxidative stress and a proinflammatory signature of astroglia, which appears to be influenced by the loss of constitutive PPAR? signaling in astrocytes. PPARγ is highly expressed in glial cells and plays a vital constitutive role in regulating cell metabolism, bioenergetics, cell survival and immune function. Treatment with a PPARγ agonist has shown efficacy in restoring behavioral outcomes and rescuing astroglia pathobiology in our r-mTBI model. Because multiple cell types express PPARγ receptors, PPARγ ligands lack the specificity needed to target astroglia specific PPARγ signaling in vivo. In this proposal, we plan to clarify the constitutive role of PPARγ in regulating astroglial responses in the healthy brain and in the context of TBI, and demonstrate whether astroglia specific PPARγ activation mitigates TBI mediated astroglia activation, inflammation, neurodegeneration and functional outcomes. We will achieve this by utilizing a tamoxifen inducible mouse model that specifically targets PPARγ activation in astrocytes. We will induce PPARγ activation inastrocytes using three therapeutic time-windows (i.e., pre-injury, early and delayed), and examine functional and pathobiological outcomes, scRNAseq profiles and functional activities of astroglia at 6 mo post-injury. In our scRNAseq study, we will compare TBI-dependent responses in the presence or absence of PPARγ activation to reveal astroglia-specific targets that correlate with favorable outcomes at the optimaltime-window of treatment, and represent novel therapeutic and translational targets. Our goal is to clarify the role of PPARγ as a regulator of astroglia pathobiology in the chronic sequelae of TBI and identify reparative mechanisms in astrocytes driving favorable outcomes that can be explored as novel astrocyte specific targets in future work, not only in TBI but ADRD where astrocyte pathobiology is a critical contributor.

重复性轻度创伤性脑损伤（r-mTBI）可在损伤停止多年后引起神经损伤，