Chemical probes to decipher PAD biology

项目总结 蛋白瓜氨酸化在炎症性疾病和癌症中增加，有证据表明这一点 翻译后修饰是导致疾病发生的主要因素。事实上，对蛋白质的抑制 瓜氨酸降低类风湿性关节炎、溃疡性结肠炎、神经病变动物模型的疾病严重程度 损害和癌症。因此，催化这种PTM的蛋白质精氨酸脱亚胺酶(PADS)代表了新的 治疗靶点。 这一更新应用的总体目标是研究蛋白质瓜氨酸化如何影响人类细胞 发信号。要解决的具体问题包括：(1)哪些蛋白质是瓜氨酸化的？(2)如何 瓜氨酸化会影响活性吗？(3)瓜氨酸化会影响蛋白分解事件吗？以及(4)我们能否产生 同工酶特异性抑制物？这些问题的答案将通过(1)发展化学蛋白质组学来获得 用于识别瓜氨酸事件的平台；(2)开发和使用遗传密码扩展平台 评估个别瓜氨酸化事件的功能后果；以及(3)开发化学探针 以及同工酶选择性PAD抑制剂来调节细胞的瓜氨酸化水平。通过解决其中的每一个 对于这些问题，国际和平研究所希望提供一个关于PAD如何对人类生物学做出贡献的整体理解。 鉴于PI的出色记录和他在PAD领域的领导地位，再加上他的 强大的合作者网络，该项目将提供新的见解和急需的研究工具 科学界。主要成果包括新的PAD生物学的发现，预计将有 对自身免疫和癌症的主要翻译影响。

PROJECT SUMMARY Protein citrullination is increased in inflammatory disease and cancer, and the evidence indicates that this post-translational modification is a major contributor to disease pathogenesis. In fact, inhibition of protein citrullination decreases disease severity in animal models of rheumatoid arthritis, ulcerative colitis, nerve damage, and cancer. Thus, the Protein Arginine Deiminases (PADs), which catalyze this PTM, represent novel therapeutic targets. The overall goal of this renewal application is to investigate how protein citrullination impacts human cell signaling. Specific questions to be addressed include: (1) What proteins are citrullinated?; (2) How does citrullination affect activity?; (3) Does citrullination impact proteolytic events? and (4) Can we generate isozyme specific inhibitors? Answers to these questions will be obtained by (1) developing chemoproteomic platforms to identify citrullination events; (2) developing and using a genetic code expansion platform to evaluate the functional consequences of individual citrullination events; and (3) developing chemical probes and isozyme selective PAD inhibitors to modulate cellular citrullination levels. By addressing each of these questions, the PI expects to provide a holistic understanding for how the PADs contribute to human biology. Given the outstanding track record of the PI and his leadership position in the PAD field, combined with his strong network of collaborators, this project will provide new insights and sorely needed research tools to the scientific community. Key outcomes include the discovery of new PAD biology, which is predicted to have major translational impacts on autoimmunity and cancer.