This is a Shannon award providing partial support for the research projects that fall short of the assigned Institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. DESCRIPTION (Adapted from the Applicant's Abstract): The loss of bone mass during aging attributing to senile osteoporosis is a serious clinical problem among the elderly. However, little is known about the cellular and molecular pathogenesis of bone loss during aging. It is thought that age-related bone loss is due to a decrease in bone formation. This proposal will test the hypothesis that age-related bone loss and development of osteoporosis are associated with the alteration of osteoblastic cell functions during aging. Much of the available information on age-related bone loss has been extrapolated from studies of either primary embryonic bone cells or immortalized bone cell lines. However, these are not relevant models for studying changes in bone cells associated with aging. In this proposal, bone cell cultures from femurs of young and old rats will be obtained and used to compare the expression of representative osteoblastic markers in cells isolated from various aged rats (Specific Aim 1). The following osteoblastic markers will be measured in these cell cultures: alkaline phosphatase activity, parathyroid hormone (PTH)-stimulated adenylate cyclase activity, collagen I synthesis, and osteocalcin secretion in response to 1,25 (OH)2D3. In addition, efforts are proposed to determine if the expression of c-fos, c-jun, jun B and jun D in bone cells decline at the basal levels, and in response to stimulation with age (Specific Aim 2). The proto-oncogene families of c-fos and c-jun, which are associated with cell proliferation and cell differentiation, have recently been suggested to play a crucial role in cell senescence. The expression of proto-oncogenes in bone cells has not been studied as a function of aging. Thus, the expression of the c-fos and c-jun proto-oncogene families will be measured under basal conditions and upon stimulation with PTH and serum. Furthermore, the distribution of different phenotypic bone cells in young and old bone tissue will be evaluated with in situ hybridization techniques (Specific Aim 3). In situ hybridization provides information on the localization of gene expression in heterogeneous tissue such as bone. Some reports have demonstrated that the bone-specific protein genes were present in different cell populations in new bone and adult bone tissue. In this proposal, the investigators will use in situ hybridization techniques to evaluate the expression of bone-specific proteins, alkaline phosphatase, osteocalcin and PTH/PTHrP receptor. The results of this work are intended to provide information on the mechanisms of age- related bone loss, which may ultimately lead to the development of preventive or treatment strategies for senile osteoporosis.
