Role of DPP4-ADA interaction in obesity-induced inflammation

摘要 DPP4抑制剂(DPP4i)是一类新型的口服抗糖尿病药物，通过 抑制DPP4介导的促胰岛素分泌激素的酶促降解。然而，非- DPP4在糖尿病中的酶功能还不是很清楚。我们和其他人最近的数据表明， DPP4的作用更加复杂，与其酶功能无关。我们发现DPP4在肥胖症中表达上调 DPP4的非酶功能可能参与了2型糖尿病的脂肪组织炎症 (T2 DM)与腺苷脱氨酶(ADA)相互作用。在其他的初步研究中，我们发现：(1)DPP4 在肥胖患者中上调；(2)造血型DPP4缺乏减少了T细胞炎症 (3)DPP4缺乏表现出对多种趋化因子的迁移活性降低。我们的 总体假设是T细胞上的DPP4促进了肥胖患者T细胞的募集和激活。在这 建议，我们将使用人源化动物模型(hDpp4KI，表达人DPP4的小鼠模型)来 剖析DPP4，特别是它的非酶功能如何与肥胖/T2 DM有关，并使用一个新的诱饵 (中东呼吸综合征冠状病毒尖峰蛋白受体结合域，MERS S-RBD)至 阻断DPP4/ADA信号转导，调节肥胖诱导的2型糖尿病炎症反应。成功执行 这项建议将为我未来的R01应用提供坚实的试点数据，并可能提供实验支持 开发了一种新的治疗方法。

ABSTRACT DPP4 inhibitors (DPP4i) are a novel class of oral anti-diabetic drugs that modulate blood glucose by suppressing DPP4-mediated enzymatic degradation of insulinotropic incretin hormones. However, the non- enzymatic function of DPP4 in diabetes is not well understood. Recent data by us and others suggest a far more complex role for DPP4, independent of its enzymatic function. We found DPP4 is up-regulated in obesity and non-enzymatic function of DPP4 might be involved in adipose tissue inflammation in type 2 diabetes (T2DM) via interaction with adenosine deaminase (ADA). In additional preliminary studies, we found: (1) DPP4 was up-regulated in obese patients; (2) Deficiency of hematopoietic DPP4 reduced T cell inflammation in the adipose tissue; (3) DPP4 deficiency showed reduced migratory activity towards multiple chemokines. Our overall hypothesis is that DPP4 on T cells promotes T cell recruitment and activation in obesity. In this proposal, we will use a humanized animal model (hDpp4KI, a mouse model expressing human DPP4) to dissect how DPP4, especially its non-enzymatic function, is implicated in obesity/T2DM and use a novel decoy (Middle Eastern Respiratory Syndrome coronavirus spike protein receptor binding domain, MERS S-RBD) to interrupt DPP4/ADA signaling and modulate obesity-induced inflammation in T2DM. Successful execution of this proposal will provide solid pilot data for my future R01 application and may provide experimental support for developing a novel therapeutic approach.