Molecular epidemiology/functional analysis of microRNAs in Non-Hodgkin's lymphoma

非霍奇金淋巴瘤中 microRNA 的分子流行病学/功能分析

• 批准号: 8448743
• 负责人: YONG ZHU
• 金额: $ 32.44万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448743
• 关键词: AIDS-Related Non-Hodgkin' s Lymphoma; Accounting; Affect; American Cancer Society; Archives; Area; Bioinformatics; Biological; Biological Markers; Caenorhabditis elegans; Case-Control Studies; Cell Line; Cells; Cessation of life; Chemoprevention; Chemopreventive Agent; Cloning; DNA; Data; Development; Epidemiologic Studies; Epidemiology; Etiology; Functional RNA; Future; Gene Mutation; Gene Targeting; Genes; Genetic; Genome; Genotype; Glean; Goals; Human; In Vitro; Incidence; Knowledge; Lymphoma; Lymphomagenesis; Malignant Neoplasms; MicroRNAs; Molecular; Molecular Epidemiology; Newly Diagnosed; Non-Hodgkin' s Lymphoma; Oncogenes; Organism; Pathway interactions; Pattern; Play; Population; Process; Publishing; Regulator Genes; Reporting; Research; Resources; Risk; Risk Factors; Role; Sample Size; Sampling; Surveys; System; Testing; Therapeutic; Time; Transfection; Tumor Suppressor Proteins; United States; Variant; Work; base; cancer risk; cancer type; cost; cost effective; expression vector; gain of function; genetic analysis; genetic association; genetic variant; genome-wide; knock-down; mortality; multidisciplinary; novel; novel diagnostics; novel therapeutics; population based; pre-miRNA; public health relevance; time use; treatment strategy; tumorigenesis; vector

DESCRIPTION (provided by applicant): The focus of the proposed study will be to identify genetic variants in microRNAs which are significantly associated with risk of Non-Hodgkin's lymphoma (NHL). Our long-term goal is to identify a panel of miRNA SNPs that may serve as novel risk biomarkers in lymphomagenesis. Archived DNA samples from our previous population-based studies of NHL will be used for the pooled genetic analysis, which allows for a large sample size and sufficient power to detect genuine associations. miRNA cloning and a vector-based delivery system will also be employed to determine the impact of all identified variants on miRNA processing and downstream regulatory capacity. Each lymphoma-associated miRNA will be interrogated using whole-genome expression microarrays and genetic networking analyses, in order to determine which biological pathways are affected by miRNA gain-of-function, and to determine the impact of each variant, particularly within the context of lymphoma-relevant pathways. In addition, the pathways regulated by each lymphoma-associated miRNA will be used to identify novel biological mechanisms involved in the etiology of lymphoma, providing new areas of future research in chemoprevention and targeted therapies. To date, very few published molecular epidemiological studies have been performed to determine whether variants in miRNAs may be associated with human cancer risk at the population level. The proposed multidisciplinary project will investigate miRNAs from a molecular epidemiological and functional genetic perspective, and the information gleaned from these studies will provide population-based evidence for the miRNA-cancer connection, and will contribute significantly to furthering our understanding of the role of miRNAs in tumorigenesis. Since DNA samples are already available for this project, the proposed study can be conducted within a relatively short time period, and will represent an extremely efficient use of time and resources. The knowledge obtained from this study has the potential to: 1) identify novel biomarkers associated with NHL risk; 2) advance our understanding of the biological mechanism involved in lymphomagenesis; and 3) provide new avenues of research which can be exploited to facilitate the development of novel chemopreventive and therapeutic strategies.

描述（由申请人提供）：拟议的研究的重点是鉴定microRNA中的遗传变异，这些变异与非霍奇金淋巴瘤（NHL）的风险显着相关。我们的长期目标是确定一组miRNA SNP，该小组可以用作淋巴细胞化的新风险生物标志物。我们以前基于人群的NHL研究中的存档DNA样品将用于合并的遗传分析，该分析允许样本量和足够的能力来检测真正的关联。也将采用miRNA克隆和基于向量的输送系统来确定所有已识别变体对miRNA加工和下游调节能力的影响。每个淋巴瘤相关的miRNA将使用全基因组表达微阵列和遗传网络分析进行询问，以确定哪些生物学途径受miRNA功能获得的影响，并确定每个变体的影响，尤其是在淋巴瘤较高途径的背景下。此外，每种淋巴瘤相关的miRNA调节的途径将用于鉴定涉及淋巴瘤病因的新型生物学机制，从而为化学预防和靶向疗法提供了未来研究的新领域。迄今为止，很少有发表的分子流行病学研究来确定miRNA中的变异是否可能与人群水平上的人类癌症风险相关。拟议的多学科项目将从分子流行病学和功能遗传学的角度研究miRNA，从这些研究中收集的信息将为miRNA-Cantcancer连接提供基于人群的证据，并将为我们对肿瘤中mirnas的作用的理解产生重大贡献。由于该项目已经可以使用DNA样本，因此可以在相对较短的时间内进行拟议的研究，并且将代表时间和资源的极有效利用。从这项研究中获得的知识具有：1）确定与NHL风险相关的新型生物标志物； 2）促进我们对淋巴作用涉及的生物学机制的理解； 3）提供新的研究途径，可以利用这些途径，以促进新型化学预防和治疗策略的发展。