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overview
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Dr. Clark’s laboratory has a long-standing interest in B cell antigen receptor (BCR) signaling and the ways in which BCR-dependent processes regulate specific cell fate decisions. In the bone marrow, Dr. Clark's research has focused on understanding how signals initiated through the pre-BCR, in conjunction with those delivered via the IL-7 receptor, coordinate cell cycle progression with immunoglobulin light chain gene recombination. This work led to the discovery of the epigenetic reader BRWD1 as a critical regulator of both Ig-kappa accessibility and the coordination of broad transcriptional programs during early and late B lymphopoiesis.
More recently, Dr. Clark’s team demonstrated that the pre-BCR initiates an IRF4-CXCR4 feedforward loop, and that CXCR4 directly signals Ig-kappa recombination. These findings fundamentally revise the canonical model of B lymphopoiesis and represent the first demonstration of a direct and independent role for CXCR4 in driving a key biological process.
In peripheral tissues, Dr. Clark has concentrated on the molecular regulation of germinal centers (GCs). His group recently identified two novel B cell populations within the dark zone that enable compartmentalization of core GC functions and uncover the molecular programs driving the GC cycle. This three-population model significantly reshapes the prevailing paradigm of GC biology. Across all areas of investigation, Dr. Clark’s laboratory has developed novel in vivo models and conducted targeted in vitro studies to achieve definitive insights into these complex processes.
On the translational front, Dr. Clark has explored how in situ adaptive immune responses contribute to tubulointerstitial inflammation in human lupus nephritis. For these studies, his group has employed deep machine learning to create innovative image analysis tools capable of quantifying and elucidating functional relationships between different T cell and antigen-presenting cell populations in situ. Notably, this bioinformatics platform achieves sensitivity and specificity approaching that of two-photon excitation microscopy (TPEM), while being applicable to the study of human disease. Additionally, Dr. Clark’s team has utilized single-cell technologies to investigate B cell selection at sites of inflammation and to examine the interplay between transcriptional state and antigenic specificity.
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