Integrative multi-omic investigation of age-related changes in trabecular bone

这个项目的最终目标是在其他新陈代谢的背景下识别与年龄相关的骨骼变化 活跃的组织。与年龄相关的骨强度下降增加了骨折的风险，每2个美国人中就有1人发生骨折 45岁以上的女性和四分之一的美国男性。我们目前识别有骨折风险的人的方法 依赖于骨矿物质密度。然而，85%的骨折患者的骨密度并不低 足以在临床上诊断为骨质疏松症，因此其他与年龄相关的骨折风险的贡献者必须 确定新的治疗方案并将其作为目标。这个项目考察了DNA中与年龄有关的差异。 骨小梁的序列、基因表达(转录组学)和蛋白质表达(蛋白质组学) 一种综合的“组学”方法将识别出更多失控的通路。 老年人个体比个体单独分析。因为它在骨骼转换方面与人类有很强的相似性， 与年龄相关的衰退性和新陈代谢方面，狒狒将被用作人类骨骼老化的模型。 目标1：确定与中年骨骼过渡相关的蛋白质相互作用网络的变化 动态平衡导致老年骨骼衰退。网络分析将确定随年龄和性别变化的路径。 目的2：评估基因组、转录组和蛋白质组数据的多组整合在描述 由衰老引起的骨骼的生物学变化。综合分析将区分网络失调 在细胞组织或相互调节的多个水平上同时发生与年龄相关的变化 在水平与病理之间，仅源于蛋白质组的差异。目标3：区分年龄- 发生在肌肉骨骼系统内的整合生物通路与 更广泛地发生的。中年和老年动物之间差异整合的基因组路径将是 与功能整合的骨骼和骨骼肌，以及骨骼和肝脏相比， 它们都是对新陈代谢有反应的组织。 通过这些重要目标的实现，这个项目将在一个新的经济分析领域培训PI (蛋白质组学)，她将与以前在基因组统计分析方面的经验相结合， 转录组和表观基因组数据。该培训将包括关于衰老生物学的课程作业和 蛋白质组、代谢组学和综合组学分析，以及在以下指导下的扩展实践培训 她的导师。在我们当前的大数据时代，对这些类型的综合组学技能的需求正在增加。这个 PI将开发必要的技能和初步数据，以竞争独立的NIH资金，以研究 代谢综合征背景下的骨老化生物学。最终，这将导致她的成功 利用多组学技术确定骨骼健康和骨折风险最早下降的长期目标 以及确定哪些生物途径可以作为干预的目标，以防止骨折和保存 老年人的健康和活力。

The ultimate goal of this project is to identify age-related changes in bone in the context of other metabolically active tissues. Age-related decline in bone strength increases risk of fractures which occur in 1 in 2 American women and 1 in 4 American men after age 45. Our current methods of identifying individuals at risk of fracture rely on bone mineral density. However, 85% of individuals with a fracture do not have bone mineral density low enough to be clinically diagnosed with osteoporosis so other contributors to age-related bone fracture risk must be identified and targeted with new treatment options. This project examines age-related differences in DNA sequence, gene expression (“transcriptomics”), and protein expression (“proteomics”) of trabecular bone in baboons to test the hypothesis that an integrated “omics” approach will identify more dysregulated pathways in elderly individuals than individual analyses alone. Because of its strong similarity to humans in bone turnover, age-related decline, and metabolism, the baboon will be used as a model for human bone aging. Aim 1: Identify changes in protein interaction networks associated with transition out of middle-age bone homeostasis to elderly bone decline. Network analyses will identify pathways that change with age and by sex. Aim 2: Evaluate utility of multi-omic integration of genomic, transcriptomic, and proteomic data in describing biological changes in bone driven by aging. Integrated analyses will differentiate between network dysregulation arising from simultaneous age-related changes at multiple levels of cellular organization or inter-regulation among the levels versus pathologies rooted solely in proteomic variation. Aim 3: Differentiate between age- related changes in integrated biological pathways occurring within the musculoskeletal system versus those occurring more broadly. Differentially integrated omic pathways between middle-aged and older animals will be compared between bone and skeletal muscle, which are functionally integrated, and between bone and liver, which are both metabolically responsive tissues. Through the accomplishment of these significant aims, this project will train the PI in a new areas of omic analysis (proteomics) which she will integrate with previous experience in the statistical analysis of genomic, transcriptomic, and epigenomic data. This training will including coursework in aging biology and workshops in proteomic, metabolomic, and integrative omics analysis plus extended hands-on training under the direction of her mentors. Demand for these types of integrative omics skills is increasing in our current “big data” era. The PI will develop the skills and preliminary data necessary to compete for independent NIH funding to study the biology of bone aging in the context of the metabolic syndrome. Ultimately, this will lead to the success of her long term goal of utilizing multi-omic technologies to identify the earliest declines in bone health and fracture risk and determining which biological pathways can be targeted for intervention to prevent fracture and preserve health and vitality among older adults.