PTHrP on normal osteoblast differentiation and function

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DESCRIPTION (provided by applicant): Ramiro Toribio, DVM, PhD intends to become an independent scientist studying endocrine hormones and their role in skeletal biology and pathology in order to support a career in academia and biomedical research. Dr. Ramiro Toribio completed a PhD in calcium regulation in 2001, is board-certified by the American College of Veterinary Internal Medicine (1999), and in 2001 joined the laboratory of Dr. Thomas Rosol in a postdoctoral position. Dr. Toribio is currently an Assistant Professor in the Department of Veterinary Biosciences, the Ohio State University. His research goals are to investigate the role of parathyroid hormone-related protein (PTHrP) on the commitment of bone marrow stromal cells (BMSCs) to the osteoblastic lineage and on osteoblast function. This concept is relevant to medicine and will have clinical applications because decreased bone mass (osteoporosis) and increased bone fragility are conditions that affect millions of Americans. This award will address important biomedical questions with regard to PTHrP and skeletal biology and it will provide Dr. Toribio with the skills necessary to become an independent investigator. Research: PTHrP was initially identified as a factor responsible for humoral hypercalcemia of malignancy (HHM). It is now recognized that PTHrP is an endocrine, paracrine, and autocrine factor with multiple physiological functions. PTHrP has been shown to exert parathyroid hormone-like actions in bone and kidney by binding to the PTH-1 receptor (PTH1R). Deletion of the PTHrP gene is lethal and results in abnormal skeletal development. Recent studies have also shown that some of the effects of PTHrP on cell function are mediated by a nuclear localization signal. Since there is limited information on the role of PTHrP on osteoblast function and our laboratory has been dedicated to study important aspects of PTHrP and bone biology, the overall hypothesis to be tested is that PTHrP is important in the commitment of BMSCs to the osteoblastic lineage and for osteoblast function. To accomplish this goal a series of studies will be performed. Aim 1 will Investigate the role of PTHrP on osteoblast differentiation and function by using BMSCs and osteoblasts from PTHrP and PTH1R knock-out mice as well as by using osteogenic and adipocytic cell lines. Aim 2 will use novel animal models to study the function of PTHrP on BMSC and osteoblast function. PTHrP gene deletion and overexpression in a cell-specific manner will provide relevant information on the role of PTHrP in bone development. Aim 3 will investigate the role of the nuclear localization signal of PTHrP on BMSC and osteoblast function. We have made considerable progress to develop genetically-engineered mice for our future studies (see preliminary data). Results from these experiments will contribute to a better understanding on the role of PTHrP in bone physiology and pathophysiology, and in the creation of new agents to treat bone disease. Environment: The Department of Veterinary Biosciences is a successful unit with extramurally funded researchers in the areas of endocrinology, immunology, virology, molecular biology, and biochemistry. Dr. Thomas Rosol's laboratory will provide an excellent environment for developing the skills necessary to become a successful independent researcher.