Investigating the transcriptional role of Ro60 in the Anti-Inflammatory Response in monocytes/macrophages – RoIn

Ro60 is involved in the pathogenesis of systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Premature cardiovascular accidents have emerged as a major cause of morbidity and mortality in both SLE and SS but the underlying molecular and cellular mechanisms remain poorly understood. Anti-Ro60 antibodies are detected in the serum and inside the cells of 40-60% of SLE and 90% of SS patients, making their detection a diagnostic tool of these disorders.
Our unpublished data demonstrate that upon pro-inflammatory stimuli, Ro60 binds to selected proximal promoters in monocytes (Mo) and macrophages (Ma) to regulate the anti-inflammatory response and cell survival. Our proteomic studies indicate that Ro60 interacts with specific proteins to enhance the transcription of specific genes.
Here we propose to characterize this novel function of Ro60 in Mo/Ma:
1. We will gain insight into the global aspect and the specificity of Ro60 transcriptional function.
2. We will investigate the binding features of promoter-associated Ro60 complex to DNA and its protein interactors by biochemical approaches.
3. We will explore the molecular and functional impact of the anti-Ro60 autoantibodies that localize into the nucleus in human Mo/Ma to gain insight into the clinical and biological relevance of such a mechanism using serum and Mo/Ma from SS patients and healthy donors.
Together, we will characterize at the molecular and cellular levels a novel promoter-associated function of Ro60 to gain insights into its impact on the Mo/Ma biology under pathophysiological conditions, and the clinical relevance for SS patients.