[R01] Mechanism of alpha5 integrin contribution to Amyotrophic Lateral Sclerosis pathology

Ente: National Institute of Neurological Disorders and Stroke

Scadenza: 2031-03-31

Importo max: 674.731 EUR

Paese: US

Descrizione

Project Summary/Abstract Amyotrophic Lateral Sclerosis (ALS) is the third most common neurodegenerative disease, with no cure and limited treatment options. While motor neurons are primarily affected, non-neuronal cells, particularly myeloid cells (microglia and peripheral macrophages), significantly influence disease progression. Our preliminary studies identified α5 integrin as a novel molecular switch that emerges in myeloid cells during ALS progression and correlates with inflammatory states in both familial and sporadic ALS patients. Importantly, blocking α5 integrin significantly extends survival in ALS mouse models. This proposal aims to define the mechanistic role of α5 integrin in ALS pathogenesis through two specific aims: 1) Define the cell type-specific contributions of α5 integrin in ALS pathogenesis using conditional knockout models to selectively delete α5 integrin in microglia and/or peripheral macrophages, and 2) Elucidate how α5 integrin regulates microglial function in ALS pathology using human iPSC-derived cellular systems. We hypothesize that α5 integrin functions as a critical molecular switch driving the transition of myeloid cells from homeostatic to disease-associated microglia (DAM) states in ALS. By combining genetic models with human iPSC-derived cellular systems, we will determine how α5 integrin influences microglial migration, phagocytosis, and interactions with motor neurons in both healthy and ALS contexts. This study represents the first comprehensive investigation of α5 integrin's role in myeloid cell function in ALS. Our preliminary data suggests that targeting α5 integrin represents a novel therapeutic strategy to modulate and slow disease progression. By elucidating the molecular mechanisms governing myeloid cell contributions to ALS pathology, we will pave the way for more effective immunomodulatory treatments for this devastating disease. Istituzione: CEDARS-SINAI MEDICAL CENTER PI: Bahareh Ajami Progetto: 7R01NS146509-02

Settori: National Institute of Neurological Disorders and Stroke

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