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: 8106946
• 负责人: YONG ZHU
• 金额: $ 34.34万
• 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/8106946
• 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; 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. PUBLIC HEALTH RELEVANCE: This work will be the first molecular epidemiologic study investigating miRNAs in non-Hodgkin's lymphoma (NHL) and will contribute significantly to advancing our understanding of the role of miRNAs in lymphomagenesis. Because of the availability of DNA samples from 2 population-based NHL case-control studies, this study is both time- and cost-effective. Both genetic association and functional analyses will be performed and the knowledge gained from this study will help us to identify new cancer biomarkers and facilitate the development of novel diagnostic and therapeutic strategies.

描述（由申请人提供）：拟议研究的重点是鉴定与非霍奇金淋巴瘤（NHL）风险显著相关的microRNA遗传变异。我们的长期目标是确定一组可能作为淋巴瘤发生新的风险生物标志物的miRNA SNP。来自我们以前基于人群的NHL研究的存档DNA样本将用于合并遗传分析，这允许大样本量和足够的能力来检测真正的关联。miRNA克隆和基于载体的递送系统也将用于确定所有鉴定的变体对miRNA加工和下游调控能力的影响。将使用全基因组表达微阵列和遗传网络分析来询问每种淋巴瘤相关的miRNA，以确定哪些生物学途径受到miRNA功能获得的影响，并确定每种变体的影响，特别是在淋巴瘤相关途径的背景下。此外，每种淋巴瘤相关miRNA调控的通路将用于识别淋巴瘤病因学中涉及的新生物学机制，为未来的化学预防和靶向治疗提供新的研究领域。到目前为止，很少有已发表的分子流行病学研究已经进行，以确定是否在人群水平的miRNA变异可能与人类癌症风险。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miRNAs，从这些研究中收集的信息将为miRNAs与癌症的联系提供基于人群的证据，并将大大有助于我们进一步了解miRNAs在肿瘤发生中的作用。由于本项目已经获得DNA样本，拟议的研究可以在相对较短的时间内进行，并将非常有效地利用时间和资源。从这项研究中获得的知识有可能：1）确定与NHL风险相关的新生物标志物; 2）促进我们对淋巴瘤发生中涉及的生物学机制的理解; 3）提供新的研究途径，可用于促进新的化学预防和治疗策略的开发。 公共卫生关系：这项工作将是第一个调查非霍奇金淋巴瘤（NHL）中miRNAs的分子流行病学研究，并将大大促进我们对miRNAs在淋巴瘤发生中作用的理解。由于从2个基于人群的NHL病例对照研究中获得了DNA样本，因此本研究具有时间和成本效益。将进行遗传关联和功能分析，从这项研究中获得的知识将有助于我们识别新的癌症生物标志物，并促进新的诊断和治疗策略的开发。