Chemical probes to decipher PAD biology

 描述（由申请人提供）：瓜氨酸蛋白在几乎所有炎性疾病以及癌症中增加，证据表明这种翻译后修饰是疾病发病机制的主要贡献者。事实上，在类风湿性关节炎、溃疡性结肠炎、神经损伤和癌症的动物模型中，瓜氨酸蛋白的抑制降低了疾病的严重程度。因此，催化这种PTM的PAD代表了新的治疗靶点。 这项提案的总体目标是建立在PI令人兴奋的研究基础上， 该项目探索了PAD生物学、生物化学和抑制作用，以进一步验证PAD作为一系列疾病的治疗靶点。此外，PI还寻求确定新的瓜氨酸化疾病生物标志物。瓜氨酸生物标志物的鉴定将允许更好，更有针对性的治疗，因为它们可用于诊断和监测这些疾病的治疗效果。 在项目期间需要解决的具体问题包括：（1）细胞中PAD是如何激活的？(2)什么样的蛋白质是PAD的底物，这种修饰如何影响它们的活性？(3)瓜氨酸化蛋白能作为疾病的生物标志物吗？以及（4）能否产生针对PAD的同工酶特异性抑制剂和基于活性的蛋白质组学探针？通过解决这些问题中的每一个，PI希望提供对PAD如何促进人类生物学的全面理解。 鉴于PI的出色记录和他在PAD领域的领导地位，加上他强大的合作者网络，该项目将为科学界提供急需的研究工具，无疑将导致发现新的PAD生物学，预计对自身免疫和癌症具有重大的翻译影响。

 DESCRIPTION (provided by applicant): Protein citrullination is increased in virtually all inflammatory diseases, as well as 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 PADs, which catalyze this PTM, represent novel therapeutic targets. The overall goal of this proposal is to build upon the PI's exciting research program that has explored PAD biology, biochemistry, and inhibition to further validate the PADs as therapeutic targets for a range of diseases. Additionally, the PI seeks to identify novel citrullinated biomarkers of disease. The identification of citrullinated biomarkers will allow for better, more tailored treatments, because they can be used to diagnose and monitor the efficacy of treatments for these diseases. Specific questions to be addressed during the project period include: (1) How are the PADs activated in cells?; (2) What proteins are PAD substrates and how does this modification effect their activity?; (3) Can citrullinated proteins be used as biomarkers of disease?; and (4) Can isozyme specific inhibitors and activity based proteomic probes be generated for the PADs?. 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 sorely needed research tools to the scientific community and will undoubtedly result in the discovery of new PAD biology that is predicted to have major translational impact on autoimmunity and cancer.