Analysis of gene expression and cell function in single cell cortical osteoblasts

描述（由申请人提供）：在未来三十年内，老龄人口的人口统计学将发生巨大变化，平均寿命将大幅延长。 年龄这一人口结构变化将导致总体医疗保健负担大幅增加，因为患有与年龄有关的疾病，包括与骨质流失有关的疾病的人数急剧增加。因此，迫切需要开发更好的治疗方法来减轻老年人的骨质流失。目前用于年龄相关的骨丢失的治疗剂如双膦酸盐在减少老年受试者的骨折方面是有效的，但不能逆转骨形成的年龄相关的减少，并且与罕见但显著的副作用相关。骨形成随年龄增长而下降的潜在机制目前仍不清楚。缺乏对机制的理解，是由于我们对调节骨形成的细胞类型是否维持细胞内稳态的知识存在额外的空白。成骨细胞是维持骨骼的一种关键细胞类型，但我们对成骨细胞在体内的生物能量学、细胞内表达的基因的特征库以及细胞和分子生理学的这些方面是否响应于骨丢失而改变的知识存在巨大的缺陷。我们的中心假设是“雌激素的丧失导致从皮质骨分离的成骨细胞的生物能量和基因表达谱的根本转变”。在这里，我们提出了两个高风险高回报的目标，以调查从流行的骨丢失模型中的小鼠股骨分离的单细胞中的细胞和分子生理学;卵巢切除小鼠。

DESCRIPTION (provided by applicant): Over the next thirty years there will be a dramatic shift in the demography of the aging population, with mean lifespan shifting to substantially older ages. This demographic shift will cause substantial increases in the aggregate health care burden, as the numbers of people suffering from age-related disease, including diseases relating to loss of bone, dramatically increase. Therefore, there is an urgent need to develop better treatments for mitigating bone loss in the elderly. Current therapeutics for age related bone loss such as the bisphosphonates, have been effective in reducing fractures in elderly subjects, but do not reverse the age- related decrease in bone formation and are associated with rare but significant side effects. The underlying mechanism responsible for the decline in bone formation with age currently remains unknown. That lack of a mechanistic understanding is confounded by additional gaps in our knowledge of whether cellular homeostasis is maintained in the cell types that regulate bone formation. The osteoblast is a one key cell type in maintaining bone, yet there is a tremendous deficit in our knowledge about what the bioenergetics are of the osteoblast in vivo, what the characteristic repertoire of genes being expressed within the cell is, and do these aspects of cell and molecular physiology change in response to bone loss. Our central hypothesis is "Loss of estrogen results in a fundamental shift in bioenergetic and gene expression profiles of osteoblasts isolated from cortical bone". Here, we propose two high-risk high-reward aims to investigate cell and molecular physiology in single cells isolated from mouse femurs in a popular model of bone loss; the ovariectomized mouse.