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.
We propose to develop single cell gene expression and mitochondrial physiological measures in a popular mouse model of bone loss, the ovariectomized mouse. We will test the hypothesis that bioenergetic parameters are changed in osteoblasts in this model in conjunction with gene expression measures at the single cell level.
|Seals, Douglas R; Melov, Simon (2014) Translational geroscience: emphasizing function to achieve optimal longevity. Aging (Albany NY) 6:718-30|