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

基本信息

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
项目类别：
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

项目摘要

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.

总体摘要骨质疏松症的主要特征是骨矿物质密度（BMD）低，其在以后的生活中的风险可能是最大的 20-40 岁时达到的骨密度峰值有力地预测了尽管女性患骨质疏松症的风险更高，但男性患骨质疏松症的风险更高。骨质疏松性骨折后的发病率和死亡率要高得多。（表观）遗传因素。大多数 BMD 遗传力（>85%）（尤其是那些特定性别的遗传力）的背后很大程度上是未知的主要是由于所使用的技术和方法的限制，针对男性骨质疏松症的研究很少。我们的一般假设是：虽然个体组学研究（基因组/转录组/表观基因组）是有用的，多组学数据的综合跨组学分析将变得更加高效和强大，不仅在识别新的风险（表观）基因/变异，但最重要的是阐明它们在人类体内的功能。该 U19 计划项目 (PPG) 的总体目标是最全面地识别/表征（外延）男性骨质疏松症风险的基因/环境因素及其功能机制。通过同时研究基因组（DNA、 Proj 1)、男性转录组-（mRNA 和 miRNA，Proj 2）和表观基因组-（DNA 甲基化，Proj 3）水平，同时考虑环境因素（项目 1-3）。我们将评估性别/种族/人群的特殊性。此外，我们将进行深入的功能研究（如项目 3 所示）。用于特定新型骨质疏松症易感性的详细分子机制和功能确认特别是，除了对个体组学数据进行最先进的分析之外。分别在项目 1-3 中，我们将超越视野，开发/应用创新的分析方法（核心 C）表征不同组学内部和之间的相互作用（例如 miRNA 甲基化的相互作用，以及 DNA 变体和 miRNA/甲基化对 mRNA 的调节）我们将（在核心 C 中）创新性地整合此类内容。跨不同组学的相互作用，以识别/表征男性骨质疏松症的（表观）遗传变异（项目 1-3）。 PPG 拥有三个支持核心：A) 行政核心；B) 临床核心；以及 C) 生物统计学和生物信息学核心。每个核心服务于所有三个项目和/或其他核心。识别人类 BMD 变化的（表观）基因/环境因素及其体内功能机制，特别是对于男性来说，对于 1）获得对基本分子的全面了解是必要且重要的和骨质疏松症风险背后的环境机制，2）发现新的途径和药物治疗目标；3) 识别（表观）遗传易感个体，以便未来进行预防和治疗干预措施可以针对并基于个人的特定（表观）基因型。此次PPG有望在创新上开辟新天地，成为刺激行业发展的先锋典范。对其他复杂疾病的类似研究所产生的数据对于老龄化和医学领域将具有无价的价值。该项目中收集的细胞研究、表型和分子数据具有重要意义和相关性。