Mitochondria proteome of ulcerative colitis associated dysplasia

溃疡性结肠炎相关发育不良的线粒体蛋白质组

• 批准号: 8374386
• 负责人: Ru Chen
• 金额: $ 21.83万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374386
• 关键词: Aging; Area; Bioinformatics; Biological Assay; Biological Markers; Cells; Chronic; Clinical; Collaborations; Colon; Colon Carcinoma; Colonoscopy; Computer-Assisted Image Analysis; Decision Making; Degenerative Disorder; Development; Disease; Dysplasia; Immunochemistry; Immunohistochemistry; Inflammatory; Intervention; Knowledge; Lead; Lesion; Malignant Neoplasms; Methods; Mitochondria; Mitochondrial Proteins; Organelles; Patients; Proteins; Proteome; Proteomics; Recommendation; Research; Research Personnel; Resources; Risk; Role; Screening procedure; Societies; Techniques; Technology; Time; Ulcerative Colitis; Work; base; cancer risk; colitis associated cancer; comparative; cost; cost effective; high risk; improved; mitochondrial dysfunction; multiplex detection; neoplastic; tumor progression

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.

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，这需要频繁的结肠镜监测这些患者，是昂贵的，耗时的，和侵入性的。异型增生的客观生物标志物将在UC患者癌症风险的管理中具有重要的临床价值。UC相关癌症从发育异常发展为癌症，并与线粒体功能障碍相关，线粒体功能障碍长期以来与退行性疾病、癌症和衰老相关。我们最近的蛋白质组学研究表明，线粒体蛋白参与UC肿瘤进展，可能是生物标志物开发的有价值的目标。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，并进一步利用这些知识进行改进，更具成本效益的监测，以区分需要结肠镜检查的UC患者子集。在拟议的研究中，将应用尖端的定量蛋白质组学和生物信息学技术来发现与UC肿瘤进展期间的前驱病变相关的异常线粒体蛋白（目的1）。将使用免疫化学（目标2）和靶向蛋白质组学（目标3）互补地表征所鉴定的异常线粒体蛋白。该项目可能导致发现蛋白质生物标志物，其在决策中具有直接的临床实用性， 结肠镜检查，因此可以潜在地降低与结肠镜检查相关的成本和患者不适。此外，提出的线粒体蛋白质组的全面分析将提高对癌症进展中线粒体蛋白质组的理解，这是我们目前信息非常有限的一个领域。所描述的研究是基于我们从溃疡性结肠炎患者中获得的独特材料资源以及已经合作了十多年的研究人员的密切合作。成功完成该提案将导致：1）更好地理解UC相关异型增生和癌症中线粒体蛋白质组的改变; 2）鉴定预测UC异型增生的生物标志物候选物，提供侵入性较小，成本效益高的方法来协助UC癌症监测。 公共卫生相关性：溃疡性结肠炎（UC）是一种慢性结肠炎性疾病，最终可导致结肠癌。因此，广泛UC患者需要每2-3年进行一次结肠镜检查，以寻找癌症和癌前病变。线粒体是重要的细胞器，产生细胞所需的大部分能量，异常的线粒体与癌症有关。与UC癌症和癌前病变相关的线粒体改变的发现和表征可能导致癌症生物标志物的发展。这些生物标志物可以用来帮助决定哪些UC患者应该接受结肠镜检查，哪些不需要。这将大大降低社会成本和患者不适，并提高针对需要干预的高危患者的能力。