Astrocytic exhaustion underlies chronic progression in autoimmune inflammation of the central nervous system

Objetivo

Progressive disability in multiple sclerosis (MS) remains an unmet clinical challenge, largely resistant to current immunomodulatory therapies targeting acute inflammation. AXhaustMS addresses a fundamental gap by investigating astrocytic exhaustion as a novel cellular mechanism underlying chronic progression in autoimmune central nervous system (CNS) inflammation. I hypothesize that astrocytes, key regulators of CNS homeostasis, enter a dysfunctional “exhaustion” state driven by chronic bystander activation, disrupting essential metabolic support networks with neurons, oligodendrocytes, and microglia.
Using the spontaneous opticospinal encephalomyelitis (OSE) mouse model that recapitulates key pathological features of progressive MS, I will comprehensively define the molecular and epigenomic signatures of exhausted astrocytes and their disrupted cellular communication networks across distinct CNS compartments and disease stages (Aim 1). I will then dissect how activation context – bystander versus direct targeting – determines astrocyte fate towards either durable, sensitized states or maladaptive exhaustion leveraging exclusive T cell receptor (TCR) transgenic mouse systems and controlled T cell transfer models (Aim 2). Finally, I will validate the functional impact of exhaustion markers through ex vivo and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene perturbation strategies, testing therapeutic reversibility (Aim 3).
This meticulous approach integrates innovative animal models, state-of-the-art multi-omics, and advanced gene editing to elucidate astrocytic dysfunction as a key driver of progressive MS. AXhaustMS has transformative potential to shift the treatment paradigm from immune suppression to cellular rehabilitation, offering new avenues for therapeutic intervention in MS and related neurodegenerative diseases characterized by chronic glial dysfunction.