Trans-omics integration of multi-omics studies for male osteoporosis

男性骨质疏松症多组学研究的跨组学整合

• 批准号: 10180814
• 负责人: HONG-WEN DENG
• 金额: $ 170.58万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10180814
• 关键词: Affect; Age; Aging; Bioinformatics; Biometry; Bone Density; Cells; Clinical; Collaborations; Complex; DNA; DNA Methylation; Data; Data Analyses; Defect; Development; Disease; Dual-Energy X-Ray Absorptiometry; Elderly; Elements; Environment; Environmental Risk Factor; Epigenetic Process; Ethnic group; Etiology; Fatty acid glycerol esters; Feasibility Studies; Future; Gene Expression; Genes; Genetic; Genetic Markers; Genome; Genotype; Goals; Heritability; Human; Individual; Intervention; Joints; Life; Limb structure; Measurement; Measures; Medical; Messenger RNA; Metabolic Bone Diseases; Methodology; Methylation; MicroRNAs; Molecular; Morbidity - disease rate; Multiomic Data; Obesity; Osteoporosis; Pathway interactions; Pattern; Phenotype; Predisposition; Prevention; Process; Proteins; Public Health; Publications; Regulation; Research; Risk; Risk Factors; Solid; Specialized Center; Specificity; Susceptibility Gene; Technology; Thinness; Time; Translating; Variant; Woman; Work; base; bioinformatics tool; bone; bone loss; bone quality; cost; druggable target; epigenome; expectation; fracture risk; gene environment interaction; genetic information; genetic testing; genetic variant; high risk; in vivo; innovation; insight; interest; mRNA Stability; male; member; men; mortality; multiple omics; novel; novel strategies; osteoporosis with pathological fracture; phenotypic data; programs; risk variant; sarcopenia; sex; targeted treatment; transcriptome

Overall Abstract Osteoporosis is mainly characterized by low bone mineral density (BMD) and its risk later in life can be most powerfully predicted by peak BMD achieved at ages 20-40. Although women have higher risk to osteoporosis, men suffer much higher morbidity and mortality rates following osteoporotic fractures. The (epi-)genetic factors underlying the majority of the BMD heritability (>85%) (especially those sex-specific ones) are largely unknown mainly due to the limitation of the technology and approaches used. Studies focusing on male osteoporosis are rare. Our General Hypothesis is that: while individual omics studies (genome/transcriptome/epigenome) are useful, integrative trans-omics analyses of multi-omics data will be much more productive and more powerful, in not only identifying novel risk (epi-)genes/variants, but also most importantly illuminating their functions in vivo in humans. The Overall Goal of this U19 program project (PPG) is to most comprehensively identify/characterize (epi- )genes/environmental factors and their functional mechanisms for male osteoporosis risk. We will pioneer a comprehensive and novel approach by investigating osteoporosis risk factors simultaneously at the genome- (DNA, Proj 1), transcriptome- (mRNA and miRNA, Proj 2), and epigenome- (DNA methylation, Proj 3) levels in males, while considering environmental factors (Proj 1-3). We will assess sex/ethnicity/population specificity of the identified (epi-)genes (Proj 1-3). Furthermore, we will perform in-depth functional studies (as exemplified in Proj 3) for detailed molecular mechanisms and functional confirmation of specific novel osteoporosis susceptibility genes/variants to be discovered. Particularly, in addition to the state-of-the-art analyses of individual omics data in Proj 1-3 respectively, we will go beyond the horizon to develop/apply innovative analytical approaches (Core C) to characterize interactions within and across different omics (such as interactions for miRNA-methylation, and regulation of mRNA by DNA variants and by miRNA/methylation). We will (in Core C) innovatively integrate such interactions across various -omics to identify/characterize (epi-)genetic variants for male osteoporosis (Proj 1-3). The PPG has three supporting cores: A) Administrative Core; B) Clinical Core; and C) Biostatistics and Bioinformatics Core. Each core serves all the three projects and/or the other cores. Identifying (epi)genes/environmental factors AND their in vivo functional mechanisms for human BMD variation, especially for men, is necessary and important for 1) gaining comprehensive insights into the fundamental molecular and environmental mechanisms underlying risk of osteoporosis, 2) discovering novel pathways and druggable targets for therapeutic cures; 3) identifying (epi-)genetically susceptible individuals, so that future preventions and interventions can be targeted to and based on individuals’ specific (epi-)genotypes. This PPG is expected to break new ground for its innovation, which serves as a pioneering example to stimulate similar studies of other complex diseases. The data generated will be invaluable for aging and medical fields for which the cells studied, phenotype and molecular data collected in this project are significant and relevant.

总体抽象 骨质疏松症主要以低骨矿物质密度（BMD）为特征，其后期的风险最多。 尽管女性患骨质疏松症的风险更高，但男性 骨质疏松性骨折后，发病率和死亡率更高。 （表演）遗传因素 大多数BMD遗传力（> 85％）（尤其是特定于性别的BMD）是未知的 主要是由于所使用的技术和方法的限制。针对雄性骨质疏松症的研究很少见。 我们的一般假设是：虽然单个OMICS研究（基因组/转录组/表观基因组）很有用，但 多摩斯数据的综合跨词分析将更加生产力和更强大，不仅在 识别新型风险（Epi-）基因/变体，但最重要的是阐明了它们在人体体内的功能。 该U19计划项目（PPG）的总体目标是最全面地识别/表征（Epi- ）基因/环境因素及其对男性骨质疏松风险的功能机制。我们将开拓 仅在基因组（DNA，， proj 1），转录组（mRNA和miRNA，proj 2）和表观基因组（DNA甲基化，proJ 3）男性水平， 同时考虑环境因素（ProJ 1-3）。我们将评估性别/种族/人口特异性 鉴定（Epi-）基因（ProJ 1-3）。此外，我们将进行深入的功能研究（如ProJ 3中的例证） 用于详细的分子机制和特定新型骨质疏松敏感性的功能确认 要发现的基因/变体。特别是，除了对单个OMICS数据的最新分析外 ProJ 1-3分别将超越地平线开发/应用创新的分析方法（核心C） 表征在不同的omics内部和跨越不同的相互作用（例如miRNA-甲基化的相互作用， 通过DNA变异和miRNA/甲基化对mRNA的调节）。我们将（在核心中）创新的整合 各种摩学的相互作用以识别/表征雄性骨质疏松症的（ProJ 1-3）的（表观）遗传变异。 PPG有三个支持核心：a）行政核心； b）临床核心； c）生物统计学和 生物信息学核心。每个核心都为所有三个项目和/或其他内核提供服务。 识别（EPI）基因/环境因素及其在人体BMD变异的体内功能机制， 特别是对于男性，对于1）获得对基本分子的全面见解是必要而重要的 以及骨质疏松症风险的潜在风险的环境机制，2）发现新型途径和可吸毒 治疗的靶标； 3）识别（表演）遗传易感人，以便未来的预防和 干预措施可以针对并基于个人的特定（表演基因型）。 预计该PPG将为其创新而打破新的基础，这是一个开创性的例子来刺激 对其他复杂疾病的类似研究。生成的数据对于老化和医疗领域是无价的 该项目中收集的细胞，表型和分子数据是重要且相关的。