Identification of Citrullinated Biomarkers of Inflammatory Disease and Cancer

描述（由申请人提供）：本申请的目标是鉴定癌症、类风湿关节炎和结肠炎的瓜氨酸化生物标志物。这一目标将通过开发一种高度实用和通用的技术来检测和表征复杂蛋白质组中的瓜氨酸化蛋白来实现。蛋白瓜氨酸化在几乎所有炎症性疾病和癌症中都增加，有证据表明这种翻译后修饰是疾病发病机制的主要因素。事实上，在类风湿关节炎、溃疡性结肠炎、神经损伤和癌症的动物模型中，抑制蛋白瓜氨酸化可降低疾病的严重程度。因此，瓜氨酸化的生物标志物很可能存在，利用这些瓜氨酸化事件进行疾病诊断提出了一种适用于多种疾病的单一挑衅策略。本文提出的方法是创新的，因为一种新的范式正在被测试-瓜氨酸化蛋白是疾病的生物标志物。此外，将开发一种使能技术，可用于识别多种疾病状态下的瓜氨酸化生物标志物。正在开发的平台比现有技术更快，更通用，提供了一种独特的策略来询问瓜氨酸化在这些疾病中的作用。此外，该技术可扩展到用质谱法鉴定和定量瓜氨酸化蛋白，这是现有技术无法实现的。因此，这个新平台不仅适用于筛选患者样本以鉴定生物标志物，而且可以适应于丰富和鉴定特定的瓜氨酸化蛋白，从而更深入地了解瓜氨酸化的功能作用。这项技术，加上疾病模型和合作者在这方面的专业知识

DESCRIPTION (provided by applicant): The goal of this proposal is to identify citrullinated biomarkers of cancer, rheumatoid arthritis and colitis. This goal will be achieved by developing a highly practical and versatile technology to detect and characterize citrullinated proteins in complex proteomes. 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 diseas severity in animal models of rheumatoid arthritis, ulcerative colitis, nerve damage, and cancer. Thus, citrullinated biomarkers most likely exist and exploiting these citrullination events for disease diagnostics presents a single provocative strategy that is applicable to multiple diseases. The approach proposed herein is innovative because a new paradigm is being tested - that citrullinated proteins are disease biomarkers. Additionally, an enabling technology will be developed that can be used to identify citrullinated biomarkers in numerous disease states. The platform being developed is faster and more versatile than existing technologies, providing a unique strategy to interrogate the role of citrullination in these diseases. Furthermore, this technology can be extended to the identification and quantification of citrullinated proteins by MS, which is not possible with existing technologies. This new platform is therefore not only applicable to screening patient samples to identify biomarkers, but can be adapted to enrich and identify specific citrullinated proteins, thereby providing deeper insight into the functional roleof citrullination. This technology, coupled with the disease models and collaborator expertise in this grant, enables the exploration of a potential paradigm-shifting outcome, whereby the detection of citrullination events provides a common diagnostic for a multitude of divergent diseases. The impact of this proposal is multifold. First, the identification of citrullinated biomarkers will alow for better, more tailored treatments, because they can be used to diagnose and monitor the efficacy of treatments for these diseases. Second, these efforts will define the 'citrullinome', thereby facilitating a greater understanding of how this modification contributes to normal and pathological processes. Third, these findings will determine if there is a common link between these disparate diseases. In summary, the funding of this proposal will ultimately provide powerful chemical probes for scientists interested in the in vivo role of protein citrullination an will have a strong translational impact on the development of diagnostics and therapeutics for numerous diseases.