Thursday, April 25, 2024
4/25/2024
Differentiation of B cell precursors into antibody-secreting B lymphocytes is a multi-stage process, and dysregulation of this intricate differentiation pathway is implicated in a wide range of immune diseases, from primary immunodeficiencies (PIDs) to autoimmune disorders such as systemic lupus erythematosus (SLE). An insufficient understanding of the molecular mechanisms that govern B cell biology is one of the critical barriers preventing development of impactful therapies against these B cell-mediated diseases. Control of gene expression by microRNAs (miRNAs) has recently emerged as a key mechanism that regulates B cell ontogenesis and effector responses. Thus, better insights into how individual miRNAs function in B cells may allow us to create novel, targeted strategies against immune diseases. The focus of this proposal is on miR-142. Using a loss-of-function genetic approach, we have established miR-142 as an essential, cell- intrinsic regulator of B cell physiology. miR-142 plays two contrasting roles in B cells - it attenuates B cell maturation, while promoting antibody responses. The objective of this proposal is to gain further insights into the role of miR-142 in B cell development and effector functions, and determine its mode of action in B cells. We have identified Wiskott-Aldrich syndrome like (WASL) gene as a bona fide target of miR-142 in B cells. WASL, like its close homolog WAS gene which is frequently mutated in patients with PIDs, encodes a multidomain protein that functions as a signaling hub that coordinates actin polymerization. Actin remodeling is important in the regulation of multiple aspects of B cell biology, including B cell maturation and antibody responses. Thus, our overall hypothesis is that miR-142, in part by targeting WASL, plays a crucial role in the regulation of B cell maturation and B cell effector responses. We will test our central hypothesis with three specific aims. In Aim 1, we will investigate the role of miR-142 in primary B cell development and define its mode of action. We will characterize B cell maturation defects in miR-142-/- mice, and link them to underlying molecular changes. Experiments proposed in Aim 2 will determine the impact of miR-142 deletion on B cell effector functions. Using mice with a conditional deletion of miR-142 in activated B cells, we will investigate the role of miR-142 in germinal center formation, immunoglobulin class-switching, and differentiation of long-term plasma cells. We will connect any observed defects in the physiology of miR-142-deficient effector B cells with changes in signaling and gene expression patterns. Finally, in Aim 3, we will define the role of WASL in miR- 142-mediated control of B cell maturation and effector responses by epistasis analysis. The proposed research is significant because it will advance our understanding of the post-transcriptional mechanisms that govern B cell development and humoral immune response. Moreover, our work is expected to establish miR-142 and its downstream target WASL as attractive pharmacological targets for treatment of B cell-mediated disorders, including PIDs and SLE.
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