Investigating how chronic inflammation induces innate immune memory in human microglia

Active Project Grant Awarded Last action

Award ID
F31AG101840
Recipient
Awarding agency
Obligated
$43,714

Award facts

Assistance listing
93.866 Aging Research
Completion date 0% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Chronic low-grade inflammation is a hallmark of neurodegenerative diseases, including alzheimer's disease. Microglia, the long-lived resident immune cells of the brain, play a central role in maintaining brain homeostasis but are particularly vulnerable to reprogramming by peripheral immune challenges. Repeated inflammatory stimuli may induce maladaptive states in microglia that persist beyond the resolution of acute inflammation and contribute to neurodegeneration. In alzheimer's disease, dysfunctional microglia are increasingly recognized as key drivers of disease progression. However, the molecular and epigenetic mechanisms that sustain these maladaptive microglial states remain poorly understood, especially in humans, because most existing studies rely on rodent models that fail to capture the complexity of human immune responses and genetic risk. To address this critical GAP, we use a novel organoid-based xenotransplantation platform that enables in vivo investigation of human microglia within a vascularized, brain-like environment. The overarching goal is to identify and manipulate molecular circuits that drive maladaptive microglial states induced by chronic inflammation. Preliminary data show that systemic LPS administration induces long-lasting transcriptional changes in human microglia, including persistent activation of EGR1. We hypothesize that chronic inflammation drives long-lasting microglial reprogramming, compromising their ability to support brain homeostasis. We further propose that this is encoded through an epigenetic reprogramming which is partially orchestrated by EGR1. We propose that targeted interventions of EGR1 can restore microglial homeostatic gene expression signatures and serve as a novel therapeutic. We will pursue two specific aims: (1) dissect molecular and epigenetic candidates responsible for chronic immune reprogramming and (2) evaluate the role of EGR1 in orchestrating a chronic immune reprogramming. This project will provide new insights into how immune reprogramming shapes human microglia states and will inform therapeutic approaches for ad and other neurodegenerative diseases.

Quick answers

Who received award F31AG101840?

F31AG101840 was awarded to The Salk Institute For Biological Studies. San Diego. California by National Institute on Aging (National Institutes of Health) on March 1, 2027.

How much is award F31AG101840 worth?

$43,714 has been obligated on F31AG101840.

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