Wednesday, February 5, 2025
2/5/2025
Project Summary (<30 lines): VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly identified inflammatory and hematologic disease caused by somatic mutations in UBA1. Individuals with UBA1 mutations have clinical manifestations similar to well-established rheumatic diseases such as rheumatoid arthritis and giant cell arteritis but have unique manifestations including elevated mortality and treatment-refractory disease. 1/14,000 individuals are affected by VEXAS syndrome, and there are no effective treatments due to a limited understanding of pathogenesis. We propose to further the mechanistic understanding of the disease as a first step in developing treatments. VEXAS syndrome is caused by hypomorphic mutations in UBA1 that lead to a reduction in global ubiquitylation. UBA1 mutations are acquired and occur in the earliest bone marrow progenitor cells, become lineage restricted, and accumulate within the myeloid lineage and are absent in lymphocytes. We have extensively studied cellular models and patient derived cells to better understand the mechanism of disease in VEXAS syndrome. We have identified multiple activated inflammatory pathways, although given the complexity of treatments and symptoms in patients, these have not revealed pathogenic processes. Similarly, in UBA1 mutant cells there is activation of the unfolded protein response likely due to accumulation of proteins intended to be degraded. Given the severity of the disease, the lack of effective therapies, and the limited utility of cellular models to date, we propose here to focus our work on our newly established mouse models of VEXAS syndrome to understand the cellular and molecular mechanisms leading to disease. To this end, we will utilize conditional knockout (cKO) UBA1 and conditional knock-in (cKI) UBA1 VEXAS mutations transgenic mouse lines to determine the contribution of specific lineages to inflammation, the types of inflammation, downstream pathways mediating inflammation and finally potential ways to reverse disease. We will study our Uba1 cKO, and cKI lines in bone marrow progenitor, myeloid, B- and T-cells and determine the role of each cell type in driving organismal inflammation (Aim 1). We will also look at these cell specific models to identify the molecular signaling pathways altered in cells mediating inflammation (Aim 2). Finally, we will utilize small molecule activators and inhibitors in candidate pathways such as ubiquitylation and the unfolded protein response to try to reverse inflammation in mouse and cellular models. Our overall goal is to better define VEXAS syndrome inflammation and molecular signing to enable improved therapies.
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