Roles of Microglial-HIF1 in TBI-Induced Immunometabolic Dysfunction Pilot

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“Roles of microglial-HIF1α in TBI-induced immunometabolic dysfunction” Traumatic brain injury (TBI) poses a significant risk for the development of neurodegenerative disorders, such as Alzheimer''s Disease (AD) and AD-related dementia (ADRD). In fact, TBI is considered one of the most influential environmental factors contributing to AD/ADRD. Moreover, the impact of TBI is exacerbated in the context of aging, which is a key factor in both the incidence and vulnerability to TBI. Understanding the cellular mechanisms underlying the increased susceptibility of the aging brain to degenerative responses following TBI remains a challenging task. Existing studies investigating TBI-related Alzheimer''s-like impairments have primarily focused on young adult rodents, which fail to accurately represent the population most at risk—aged individuals. Our previous research has shown that the aged brain exhibits a higher susceptibility to neuroimmunological sequelae following TBI compared to younger counterparts. Using an aged TBI rodent model, we have successfully reproduced several key features of Alzheimer''s- like sequelae, including chronic memory impairment, heightened neuroinflammation, gliosis, phosphorylated tau, and microglial phenotypes consistent with both human and mouse models of Alzheimer''s disease. Notably, our preliminary data indicate that a specific subset of microglia, which displays a chronically reactive phenotype, exhibits increased expression of the transcription factor HIF1α. HIF1α is known to drive metabolic alterations in immune cells in response to environmental cues, a process referred to as ''immunometabolism''. While HIF1α''s regulatory role in peripheral immune cells and its involvement in non-CNS disorders are well-documented, its intrinsic regulation of microglial responses to TBI and the resulting consequences are poorly understood. Our overarching hypothesis is that HIF1α plays a pivotal role in driving chronic microglial reactivity in the aged brain following TBI, thereby contributing to both cell-autonomous and non-cell-autonomous neurodegenerative sequelae. To test this hypothesis, we propose 2 specific aims using our novel cell-type- specific microglial conditional knockout of HIF1α (cKO): 1) to assess the impact of HIF1α on microglial spatial heterogeneity, 2) to investigate the deleterious shifts in microglial metabolism resulting from HIF1α dysregulation. Collectively, we anticipate that the findings from our proposed studies will fill critical knowledge gaps related to the HIF1α-driven immunometabolic response of microglia in the aged brain following TBI.
Effective start/end date10/23/232/29/24


  • National Institute of General Medical Sciences


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