[F31] Molecular Reprogramming of Microglia in Neurodegeneration
Ente: National Institute on Aging
Scadenza: 2027-11-26
Importo max: 34.114 EUR
Paese: US
Descrizione
PROJECT ABSTRACT
Microglia, the brain's primary immune cells, play various roles in Alzheimer's Disease (AD) with protective and
neurodegenerative outcomes. Our lab recently identified a neurodegenerative subset of microglia
characterized by the activation of the integrated stress response (ISR), a cellular stress response pathway.
Notably, genetic and environmental AD risk factors, including the strongest genetic risk factor, APOE4, can
activate ISR in microglia. We found that repeated microglial ISR activation, mimicking chronic exposure to
these risk factors, worsens AD-related pathologies, while its inhibition mitigates these effects. These results
suggest that ISR (induced by AD risk factors) could reprogram microglia toward a neurodegenerative state.
However, whether and how repeated ISR activation can reprogram microglia remains unclear.
A primary mechanism that mediates long-term cellular reprogramming is epigenetics, which involves the
modification of DNA and DNA-bound histone proteins. In elucidating potential ISR-induced epigenetic changes,
I found that chronic ISR activation increases repressive histone marks associated with closed chromatin and
reduces activating marks linked to open chromatin. This indicates a shift toward a closed, heterochromatic
state, which has been ultrastructurally observed in stressed microglia. In parallel, I found significant alterations
in key metabolites involved in the regulation of these epigenetic modifications. Based on these findings, I
hypothesize that chronic ISR activation in microglia promotes heterochromatic histone methylation in a
metabolite-dependent manner. This proposal will address my hypothesis through two specific aims: Aim 1 will
determine the impact of ISR on the in vitro metabolite production and consumption
rates
and in vivo microglial
metabolomics. Aim 2 will determine the impact of ISR on metabolite-driven epigenetic changes in microglia by
global and genome-wide mapping of histone modifications in vivo.
Overall, this proposal will elucidate the potential role of the metabolic-epigenetic axis in ISR-dependent
microglial reprogramming, providing insights into the mechanisms underlying neurodegeneration and informing
potential therapeutic strategies. Combined with a comprehensive training plan that includes technical and
scientific learning, as well as career development opportunities, this research training will equip me with the
skills and expertise necessary to pursue a successful career as an independent scientist in academia.
Istituzione: ADVANCED SCIENCE RESEARCH CENTER
PI: Leen Aljayousi
Progetto: 1F31AG099702-01
Settori: National Institute on Aging
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