[F31] Investigating the Role of Slc4a4 in Multiple Sclerosis
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2028-07-27
Importo max: 50.114 EUR
Paese: US
Descrizione
ABSTRACT
Multiple Sclerosis (MS) is one of the most common autoimmune diseases affecting the central nervous system,
impacting approximately 2.5 million people worldwide. It is characterized by immune cell-driven inflammatory
demyelination and axonal degeneration, leading to a spectrum of motor, sensory, and cognitive deficits. A key
pathological hallmark of MS is increased blood-brain barrier (BBB) permeability. The BBB, composed of
multiple cell types, including astrocytes, is critical for maintaining CNS homeostasis. Astrocytic dysfunction has
been implicated in BBB impairment across several CNS disorders. Recent evidence suggests that Slc4a4, an
astrocyte-enriched gene, plays an essential role in regulating BBB integrity during brain injury. However, its
involvement in MS pathology and progression remains unexplored. To address this, we combined a novel
astrocyte-specific Slc4a4 conditional knockout (Slc4a4-cKO) mouse model with the experimental autoimmune
encephalomyelitis (EAE) model, a well-established MS model that recapitulates key clinical and pathological
features of the disease. Our preliminary data reveal that Slc4a4-cKO mice exhibit more severe EAE clinical
symptoms, including heightened blood-protein leakage, reduced expression of endothelial tight junction
markers, and increased demyelination. Furthermore, bulk RNA sequencing of Slc4a4-cKO mice post-EAE
induction highlights an enrichment of genes associated with endothelial cell dysfunction, although the
underlying mechanisms remain unclear. To bridge this knowledge gap, I propose three aims to investigate the
role of astrocytic Slc4a4 in MS progression. First, I will characterize Slc4a4 expression in human MS tissue
and assess EAE pathology across different disease stages in Slc4a4-cKO mice. Next, I will explore whether
overexpression of astrocytic Slc4a4 confers therapeutic benefits in EAE. Finally, I will examine the role of
Edn1, a candidate gene upregulated in Slc4a4-cKO mice, along with its associated receptors, in human MS
and during EAE in Slc4a4-cKO mice. Additionally, I will test whether pharmacological or genetic inhibition of the
Edn1 pathway can rescue the exacerbated EAE phenotypes in Slc4a4-cKO mice. Altogether, these studies aim
to uncover the Slc4a4 pathway as a potential mechanism underlying astrocyte-driven BBB dysfunction and MS
pathogenesis, potentially identifying new therapeutic targets for this disease.
Istituzione: BAYLOR COLLEGE OF MEDICINE
PI: Roshan Ailani
Progetto: 5F31NS145624-02
Settori: National Institute of Neurological Disorders and Stroke
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