PTHrP on normal osteoblast differentiation and function

描述(由申请人提供)： 拉米罗·托里比奥博士打算成为一名研究内分泌激素及其在骨骼生物学和病理学中的作用的独立科学家，以支持在学术界和生物医学研究领域的事业。拉米罗·托里比奥博士于2001年完成钙调节博士学位，1999年获得美国兽医学院董事会认证，并于2001年加入Thomas Rosol博士的实验室担任博士后职位。托里比奥博士目前是俄亥俄州立大学兽医生物科学系的助理教授。他的研究目标是研究甲状旁腺激素相关蛋白(PTHrP)在骨髓基质细胞(BMSCs)向成骨细胞谱系的承诺和对成骨细胞功能的作用。这一概念与医学相关，并将有临床应用，因为骨量减少(骨质疏松症)和骨脆性增加是影响数百万美国人的疾病。该奖项将解决与PTHrP和骨骼生物学有关的重要生物医学问题，并将为托里比奥博士提供成为一名独立研究人员所需的技能。研究：PTHrP最初被确定为恶性体液高钙血症(HHM)的一个因素。目前认为PTHrP是一种内分泌、旁分泌和自分泌因子，具有多种生理功能。PTHrP通过与PTH-1受体(PTH1R)结合，在骨骼和肾脏发挥甲状旁腺激素样活性。PTHrP基因的缺失是致命的，会导致骨骼发育异常。最近的研究也表明，PTHrP对细胞功能的一些影响是由核定位信号介导的。由于目前关于PTHrP在成骨细胞功能中的作用的信息有限，而我们的实验室一直致力于研究PTHrP和骨生物学的重要方面，因此有待检验的总体假设是，PTHrP在BMSCs向成骨细胞谱系和成骨细胞功能的承诺中发挥重要作用。为了实现这一目标，将进行一系列研究。目的1利用PTHrP和PTH1R基因敲除小鼠的BMSCs和成骨细胞，以及成骨和脂肪细胞系，研究PTHrP在成骨细胞分化和功能中的作用。目的2利用新型动物模型研究甲状旁腺素rP对骨髓间充质干细胞和成骨细胞功能的影响。PTHrP基因的细胞特异性缺失和过表达将为研究PTHrP在骨发育中的作用提供相关信息。目的3研究PTHrP核定位信号在骨髓间充质干细胞和成骨细胞功能中的作用。我们在为未来的研究开发基因工程小鼠方面取得了相当大的进展(见初步数据)。这些实验的结果将有助于更好地理解PTHrP在骨生理学和病理生理学中的作用，并有助于创造治疗骨病的新药物。环境：兽医生物科学系是一个成功的单位，拥有内分泌学、免疫学、病毒学、分子生物学和生物化学领域的外部资助的研究人员。托马斯·罗索尔博士的实验室将为培养成为一名成功的独立研究人员所需的技能提供一个极好的环境。

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.