Epigenetic Signature of Non-Hodgkin's Lymphomas

非霍奇金淋巴瘤的表观遗传特征

• 批准号: 7061219
• 负责人: CHARLES W CALDWELL
• 金额: $ 34.06万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-10 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061219
• 关键词: B cell lymphoma; CpG islands; DNA methylation; amidohydrolases; biotechnology; cell line; clinical research; flow cytometry; functional /structural genomics; gene induction /repression; genetic transcription; human subject; human tissue; immunomagnetic separation; microarray technology; molecular biology information system; nonHodgkin' s lymphoma; technology /technique development

DESCRIPTION (provided by applicant) Non-Hodgkin's lymphoma (NHL) is the fifth most common malignancy in the United States, accounting for an estimated 55,000 new cases and 26,000 deaths in the year 2001. Although advances in cancer treatment over the past several decades have improved outcomes for many patients with hematologic malignancies, most patients with NHL relapse and ultimately die from their disease. The challenge remains to develop targeted therapies that are both more effective and less toxic. The overall goal of this application is to further develop and test an innovative microarray tool to determine DNA methylation of CpG island promoters and 1st exon regions of important genes that affect transcriptional silencing, but may potentially be reversible by pharmacological demethylation therapies. This microarray chip can measure both DNA methylation and gene expression, and hence can provide direct evidence of methylation-dependent gene silencing and reversal. Another innovation includes development of a laboratory information system for DNA methylation based on a data model and schema compliant with an evolving international consensus on microarray standards. This will provide robust and flexible data storage and XML-tagged information sharing options for further collaborative investigations. We propose to merge epigenomic and computational technologies that can form a valuable clinical laboratory tool for assessment of NHLs. An interdisciplinary team will apply computational research methods to leverage the biomedical content to identify novel and highly selective lymphoma-related epigenetic changes in specific CpG islands that may affect gene function, and furthermore, may be potentially reversed by pharmacologic interventions. The new microarrays and computational tools developed will be widely shared among other investigators around the world. One of the greatest intellectual challenges to investigations such as this is to extract the fullest meanings and implications of all available data. The 1-year R21 phase demonstrates the proof-of-concept using 2 classes of indolent NHLs and provides quantifiable, defined milestones. The 4-year R33 phase will further enhance the microarray system, examine additional classes of indolent NHLs, and determine an Epigenomic Signature of Lymphomas to improve classification, prognostic prediction, and potentially therapeutic choices in human NHL that can improve on clinical outcomes.

描述（由申请人提供） 非霍奇金淋巴瘤（NHL）是美国第五常见的恶性肿瘤，2001年估计有55，000例新发病例和26，000例死亡。尽管过去几十年来癌症治疗的进展改善了许多恶性血液病患者的预后，但大多数NHL患者复发并最终死于疾病。挑战仍然是开发更有效和毒性更小的靶向治疗。本申请的总体目标是进一步开发和测试创新的微阵列工具，以确定影响转录沉默的重要基因的CpG岛启动子和第一外显子区域的DNA甲基化，但可能通过药理学去甲基化疗法可逆。该微阵列芯片可以同时测量DNA甲基化和基因表达，因此可以提供甲基化依赖的基因沉默和逆转的直接证据。另一项创新包括开发一个基于数据模型和模式的DNA甲基化实验室信息系统，该系统符合不断发展的国际微阵列标准共识。这将为进一步的合作调查提供强大而灵活的数据存储和XML标记的信息共享选项。我们建议合并表观基因组和计算技术，可以形成一个有价值的临床实验室工具评估NHL。一个跨学科的团队将应用计算研究方法来利用生物医学内容，以确定特定CpG岛中可能影响基因功能的新型和高度选择性的淋巴瘤相关表观遗传变化，并且可能通过药理学干预逆转。新开发的微阵列和计算工具将在世界各地的其他研究人员中广泛共享。对这类调查的最大智力挑战之一是从所有可用数据中提取最充分的含义和含义。1年R21阶段使用2类惰性NHL证明了概念验证，并提供了可量化的定义里程碑。4年的R33阶段将进一步增强微阵列系统，检查惰性NHL的其他类别，并确定淋巴瘤的表观基因组特征，以改善人类NHL的分类，预后预测和潜在的治疗选择，从而改善临床结局。