PROJECT SUMMARY Immune thrombotic thrombocytopenic purpura (iTTP) is a rare but potentially fatal blood disorder, resulting from autoantibodies against ADAMTS13, a plasma metalloprotease that cleaves endothelial von Willebrand factor. Despite progresses being made in past decades, major gap remains in our understanding the pathogenesis of iTTP. The proposed study will test the hypotheses that: 1) distinct molecular signatures in the complementarity determining region (CDR)-3 and the VDJ rearrangements in the variable regions of immunoglobulins (Ig) against ADAMTS13 determine their functionalities (e.g., the inhibitory vs. activating) in patients with iTTP; 2) the abnormalities in ANKRD26 and 36 gene family, initially identified to associate with hereditary thrombocytopenia, may also play a role in pathogenesis of iTTP, likely through disruption of megakaryocytopoiesis and enhanced immune inflammatory responses. The proposed study will use various cutting-edge tools and animal models to test these hypotheses. The results of the proposed study will shed new light on pathogenesis of iTTP and other immune thrombotic disorders. The findings may help develop novel strategies for therapeutic interventions for such disorders.

PROJECT NARRATIVE The overall goal of the proposed study is to better understand the molecular pathogenesis of immune thrombotic thrombocytopenic purpura (iTTP) using various biochemical, molecular and cellular biological tools, and animal models, as well as iTTP patients. The project will focus on identifying the structural signatures and mechanism of action of human monoclonal IgG antibodies isolated through single B cell Ig sequencing, and uncovering the potential role of ANKRD26/36 gene family in the zebrafish and murine models of iTTP. We believe that the results of the proposed study may change how we manage patients with iTTP in the future.