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THE ROLE OF PTEN IN MICROGLIAL PATHOBIOLOGY AFTER EXPOSURE TO REPETITIVE MILD TBI

PTEN 在反复轻度 TBI 暴露后微胶质病理学中的作用

基本信息

批准号：
10511758
负责人：
Joseph O Ojo
金额：
$ 16.34万
依托单位：
ROSKAMP INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511758
关键词：
1-Phosphatidylinositol 3-Kinase Address Alzheimer&apos s Disease Alzheimer&apos s disease risk Animal Model Astrocytes Automobile Driving Autophagocytosis Autopsy Biochemical Markers Bioenergetics Blood - brain barrier anatomy Blood Vessels Cell Survival Cells Chronic Clinical Clinical Trials Consultations Cre-LoxP Cytokine Signaling Data Development Disease Disease associated microglia Ensure Event Exposure to Future Genes Goals Human Inflammation Inflammatory Inflammatory Response Injury Intervention Investigation Lead Learning Lipids Mediating Memory Microglia Modeling Molecular Bank Myeloid Cells Nerve Degeneration Nervous System Trauma Neurodegenerative Disorders Neurologic Deficit Neurologic Dysfunctions Neurons Outcome PTEN gene Pathogenesis Pathology Patients Performance Pharmacology Phenotype Phosphoric Monoester Hydrolases Pilot Projects Play Pre-Clinical Model Research Design Retrospective Studies Risk Factors Role Sensorimotor functions Signal Transduction Specificity Synapses Tamoxifen Therapeutic Time TimeLine astrogliosis axon injury base brain cell cell type density functional outcomes genetic signature human model inhibitor lipid metabolism mild traumatic brain injury mouse model neurobehavioral neuroinflammation new therapeutic target novel pre-clinical prevent prophylactic response response to injury single cell analysis tau Proteins therapeutic target transcriptomics translational potential treatment strategy

项目摘要

Repetitive mild traumatic brain injury (r-mTBI) is one of the strongest risk factors for developing neurodegenerative diseases. To date, no disease modifying therapies have been developed to prevent the long- term consequences of TBI. There is a need to advance our current understanding of the cellular mechanisms driving the long-term neurological deficits after TBI, as this could lead to the identification of novel therapeutic targets. Neuroinflammation mediated by resident microglia is a common feature of human and animal models of TBI. Factors governing the propagation and persistence of disease associated microglial responses in the chronic sequelae of TBI remain elusive. We have established a mouse model of r-mTBI that recapitulates many features of human TBI and thus represents a translationally relevant preclinical platform. From this model we have generated a molecular library of microglia gene profiles, at a range of timepoints post-injury that provides a unique and detailed time-course of the microglial neuroinflammatory response to r-mTBI. Particularly, we reveal deficits in energy bioenergetics, cytokine signaling, lipid metabolism, and a pro-inflammatory signature of microglia at chronic timepoints, which appear to be driven by the activation of Phosphatase and Tensin Homolog (PTEN) signaling. PTEN is a lipid phosphatase that antagonizes phosphatidylinositol 3-Kinase signaling, a critical node vital for regulating cell survival, energy bioenergetics, autophagy and inflammation. PTEN is highly expressed in myeloid cells, and its dysregulation can trigger the activation of inflammatory responses. Multiple cell types express PTEN, thus PTEN inhibitors lack the specificity needed to target PTEN signaling in microglia. In a pilot study, we have shown that PTEN deletion in myeloid cells after 1 mo dampens disease associated microglial responses and proinflammatory signature in our model. In this new application, we plan to extend these studies to further clarify the role of PTEN in regulating microglia responses in the context of TBI and demonstrate whether microglia specific PTEN deletion can mitigate TBI mediated neuroinflammation/neurodegeneration and chronic functional outcomes. We will compare TBI- dependent responses in the presence or absence of PTEN deletion to reveal microglial specific targets that correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will achieve this by utilizing a tamoxifen inducible mouse model that will specifically target PTEN deletion in microglia and not other myeloid cells (Hexbcre+/PTENfl/fl). We will induce PTEN deletion using three therapeutic time-windows (i.e., pre-injury, early and delayed), and examine functional and pathobiological outcomes, scRNAseq profiles and functional activities of microglia at 6 mo post-injury. Our goal is to clarify the role of PTEN as a negative regulator of microglial pathobiology in the chronic sequelae of r-mTBI, and to identify unique gene signatures and reparative mechanisms in microglia induced by PTEN deletion that can be explored as novel microglial specific targets in TBI and other neurodegenerative diseases where neuroinflammation is a critical contributor.

重复性轻度创伤性脑损伤（r-mTBI）是发展中最强的危险因素之一