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

该项目的最终目标是确定与年龄相关的变化，在骨的背景下，其他代谢 活性组织骨强度下降增加了骨折的风险，每2个美国人中就有1个发生骨折。 女性和四分之一的美国男性在45岁之后。我们目前识别有骨折风险的个体的方法 依赖于骨密度。然而，85%的骨折患者的骨密度并不低 足以被临床诊断为骨质疏松症，因此其他与年龄相关的骨折风险的贡献者必须 确定并有针对性地提供新的治疗方案。这个项目研究了DNA中与年龄相关的差异 序列、基因表达（"转录组学"）和蛋白质表达（"蛋白质组学"）。 狒狒来测试这一假设，即一个综合的"组学"方法将确定更多的失调途径， 老年人比单独的个体分析。由于它在骨转换方面与人类非常相似， 与年龄相关的衰退和新陈代谢，狒狒将被用作人类骨骼衰老的模型。 目的1：确定与中年骨过渡相关的蛋白质相互作用网络的变化 体内平衡对老年人骨质衰退的影响。网络分析将确定随年龄和性别而变化的途径。 目的2：评估基因组、转录组和蛋白质组数据的多组学整合在描述 由衰老驱动的骨骼生物学变化。综合分析将区分网络失调 由细胞组织或相互调节的多个水平上同时发生的年龄相关变化引起 与仅仅源于蛋白质组变异的病理学之间的差异。目标3：区分年龄- 肌肉骨骼系统内发生的综合生物学途径的相关变化与 更广泛地发生。中年和老年动物之间的差异整合组学途径将是 骨和骨骼肌之间的比较，这是功能整合，骨和肝脏之间， 这两种组织都有代谢反应。 通过这些重要目标的实现，本项目将在新的组学分析领域对PI进行培训 （蛋白质组学），她将与以前的经验，在基因组学的统计分析， 转录组学和表观基因组学数据。该培训将包括老化生物学课程和 蛋白质组学、代谢组学和整合组学分析，以及在以下指导下的扩展实践培训： 她的导师们在我们当前的"大数据"时代，对这些类型的综合组学技能的需求正在增加。的 PI将开发必要的技能和初步数据，以竞争独立的NIH资金，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 长期目标是利用多组学技术来识别骨骼健康和骨折风险的早期下降 并确定哪些生物途径可以作为干预的目标，以防止骨折和保护 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.