Lymph Node Stromal Cells in the Pathogenesis, Diagnosis, and Treatment of Unicentric Castleman Disease - Project Summary/Abstract The goal of the proposed five-year training plan is to provide the foundation for an independent, R01-funded research career as an academic physician-scientist studying the impact of lymphoid tissue stromal cells on human health and disease. I am an Instructor of Medicine with a plan to promotion to Assistant Professor in July 2025. This career development award will help establish my expertise in lymph node stroma and Castleman Disease, a rare, poorly understood blood disorder. Given the defining histologic changes in lymph node stromal cells in Castleman and recent genetic evidence of non-hematopoietic clonality, Castleman Disease is ground to establish roles for these cells in human disease pathogenesis. This training includes advancing my technical skills in bioinformatics and spatial transcriptomics in addition to advancing my expertise in lymph node stromal cells. To investigate the role of lymph node stromal cells in Castleman Disease, I am ideally positioned under the mentorship of Dr. Ivan Maillard, who has deep experience with lymph node stromal cells, and my co-mentor, Dr. David Fajgenbaum, a leader in Castleman Disease. In addition, I have assembled a mentoring committee and network of collaborators with complementary skills to advance my research and career development. I propose to investigate whether somatic mosaicism of non-hematopoietic lymph node stromal cells contributes to the pathogenesis of Castleman Disease. Castleman is a rare, life-threatening lymphoproliferative disorder where the abnormal histological appearance of lymph node stromal cells is a key hallmark of the diagnosis. In the unicentric form of Castleman Disease, where only one lymph node station is affected, recent genetic studies identified apparent clonality, including a kinase-domain PDGFRB mutation, within the non-hematopoietic cells in the lymph node. This suggests that the histologic lymph node stromal cell changes are not simply correlative, but may play an active role in disease pathogenesis. I hypothesize that selected lymph node stromal cells clonally expand in Unicentric Castleman Disease and that activating PDGFRB mutations can cause this expansion and increase cytokine production to elicit polyclonal lymphoproliferation. I will test this hypothesis by determining the cellular identity, clonality, and prevalence of expanded lymph node stromal cells (Aim 1) and identifying the functional consequences of mutant PDGFRβ signaling (Aim 2). These studies will advance our understanding of Castleman Disease’s etiology to uncover better diagnostics and therapies that help patients. My unique position as a clinician caring for Castleman Disease patients and researcher under the mentorship of Drs. Maillard and Dr. Fajgenbaum make me particularly well-suited to pursue the proposed research. To generate preliminary data, I have developed new techniques to study lymph node stromal cells in human tissue, with a first-author publication in the European Journal of Immunology. The expertise and techniques in lymph node stromal cells I will build in this proposal will help me transition towards independence as I look toward a future studying their roles in lymphoma.
