Pathogenesis of thrombotic microangiopathies

项目摘要 免疫性血栓性血小板减少性紫癜（iTTP）是一种罕见但可能致命的血液疾病， 来自抗ADAMTS 13的自身抗体，ADAMTS 13是一种切割血管内皮细胞的血浆金属蛋白酶 因子尽管在过去几十年中取得了进展，但我们在理解 iTTP的发病机制。拟议的研究将测试以下假设：1）在不同的分子签名， 互补决定区（CDR）-3和可变区中的VDJ重排， 抗ADAMTS 13的免疫球蛋白（IG）决定它们的功能（例如，抑制与激活）， ANKRD 26和36基因家族的异常，最初被鉴定为与iTTP相关， 遗传性血小板减少症也可能在iTTP的发病机制中发挥作用，可能是通过破坏 巨核细胞生成和增强的免疫炎症反应。该研究将使用各种 尖端的工具和动物模型来测试这些假设。这项研究的结果将有助于 对iTTP和其他免疫血栓性疾病的发病机制有了新的认识。这些发现可能有助于开发 用于此类疾病的治疗干预的新策略。

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.