Mitochondria proteome of ulcerative colitis associated dysplasia

描述（由申请人提供）：广泛性溃疡性结肠炎（UC）患者患结肠癌的风险显著增加。目前的筛查建议需要对这些患者进行频繁的结肠镜检查，这是昂贵、耗时和侵入性的。一个客观的非典型增生生物标志物对UC患者的癌症风险管理具有重要的临床价值。uc相关的癌症从发育不良发展为癌症，并与线粒体功能障碍有关，线粒体功能障碍长期以来与退行性疾病、癌症和衰老有关。我们最近的蛋白质组学研究表明，线粒体蛋白参与UC肿瘤的进展，可能是生物标志物开发的有价值的靶点。本研究的目的是更好地了解线粒体蛋白在慢性UC肿瘤进展中的作用；进一步，利用这些知识进行改进，更经济有效的监测，以区分需要结肠镜检查的UC患者和不需要结肠镜检查的患者。在这项研究中，尖端的定量蛋白质组学和生物信息学技术将被应用于发现UC肿瘤进展过程中与前体病变相关的异常线粒体蛋白（目的1）。鉴定出的异常线粒体蛋白将利用免疫化学（目的2）和靶向蛋白质组学（目的3）进行互补表征。该项目可能会导致发现具有直接临床应用价值的蛋白质生物标志物

DESCRIPTION (provided by applicant): Patients with extensive ulcerative colitis (UC) have a substantially increased risk of colon cancer. The current screening recommendations, which require frequent colonoscopic surveillance of these patients, are expensive, time consuming, and invasive. An objective biomarker of dysplasia would have great clinical value in the management of cancer risk in UC patients. UC-associated cancer progresses from dysplasia to cancer and is associated with mitochondrial dysfunction, which has long been associated with degenerative diseases, cancer, and aging. Our recent proteomics studies reveal that mitochondrial proteins are involved in UC neoplastic progression and could be valuable targets for biomarker development. The objectives of this research are to better understand the role of mitochondrial proteins underlying the neoplastic progression in chronic UC; and further, to employ this knowledge for improved, more cost effective surveillance-to differentiate the subset of UC patients who need colonoscopy from those who do not. In the proposed study, cutting-edge quantitative proteomics and bioinformatics technologies will be applied to discover aberrant mitochondrial proteins that are associated with precursor lesions during UC neoplastic progression (Aim 1). The identified aberrant mitochondrial proteins will be complementarily characterized using immunochemistry (Aim 2) and targeted proteomics (Aim 3). This project may lead to the discovery of protein biomarkers with direct clinical utility in decision-making for colonoscopy and thus could potentially reduce the cost and patient discomfort associated with colonoscopy. Moreover, the proposed comprehensive analysis of mitochondrial proteome will improve the understanding of the mitochondrial proteome in cancer progression, an area for which we currently have very limited information. The study described is based on our unique resource of material obtained from ulcerative colitis patients and the close-knit collaboration of investigators who have been working together for more than ten years. Successful completion of this proposal will lead to: 1) better understanding of alterations in mitochondrial proteome in UC associated dysplasia and cancer; 2) identification of biomarker candidates to predict UC dysplasia, providing a less invasive, cost effective method to assist UC cancer surveillance. PUBLIC HEALTH RELEVANCE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that can eventually cause colon cancer. Because of this, patients with extensive UC require colonoscopy every 2-3 years to look for cancer and pre-cancer. Mitochondria are important organelles that generate most of the energy a cell needs, and abnormal mitochondria have been associated with cancer. Discovery and characterization of alterations in mitochondria associated with UC cancer and pre-cancers could lead to the development of cancer biomarkers. Such biomarkers could be used to help decide which UC patients should have a colonoscopy and which don't need it. This would greatly reduce costs to society and patient discomfort, and improve the ability to target high-risk patients who need intervention.