PTHrP on normal osteoblast differentiation and function

PTHrP 对正常成骨细胞分化和功能的影响

• 批准号: 6933934
• 负责人: RAMIRO Eliseo TORIBIO
• 金额: $ 12.61万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933934
• 关键词: adipocytes; apoptosis; bone marrow; cell differentiation; cell line; cell proliferation; confocal scanning microscopy; connective tissue cells; flow cytometry; gene deletion mutation; gene targeting; genetically modified animals; histochemistry /cytochemistry; laboratory mouse; osteoblasts; parathyroid hormone related protein; parathyroid hormones; polymerase chain reaction; radiography; terminal nick end labeling; tissue /cell culture; western blottings

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.

描述（由申请人提供）： Ramiro Toribio，DVM，PhD 打算成为一名独立科学家，研究内分泌激素及其在骨骼生物学和病理学中的作用，以支持学术界和生物医学研究的职业生涯。 Ramiro Toribio 博士于 2001 年获得钙调节博士学位，并获得美国兽医内科医学院委员会认证（1999 年），并于 2001 年加入 Thomas Rosol 博士的实验室担任博士后职位。 Toribio 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) 对骨髓基质细胞 (BMSC) 向成骨细胞谱系的定向和成骨细胞功能的作用。这个概念与医学相关，并将具有临床应用，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病症。该奖项将解决有关 PTHrP 和骨骼生物学的重要生物医学问题，并将为 Toribio 博士提供成为独立研究者所需的技能。 研究：PTHrP 最初被确定为导致恶性肿瘤体液高钙血症 (HHM) 的一个因素。目前公认PTHrP是一种具有多种生理功能的内分泌、旁分泌和自分泌因子。 PTHrP 已被证明通过与 PTH-1 受体 (PTH1R) 结合而在骨骼和肾脏中发挥甲状旁腺激素样作用。 PTHrP 基因的缺失是致命的，并会导致骨骼发育异常。最近的研究还表明，PTHrP 对细胞功能的一些影响是由核定位信号介导的。由于关于 PTHrP 对成骨细胞功能的作用的信息有限，并且我们的实验室一直致力于研究 PTHrP 和骨生物学的重要方面，因此要测试的总体假设是 PTHrP 在 BMSC 向成骨细胞谱系的定向和成骨细胞功能中发挥重要作用。为了实现这一目标，将进行一系列研究。目标 1 将通过使用 PTHrP 和 PTH1R 敲除小鼠的 BMSC 和成骨细胞以及成骨细胞和脂肪细胞系来研究 PTHrP 对成骨细胞分化和功能的作用。目标2将使用新型动物模型来研究PTHrP对BMSC和成骨细胞功能的作用。 PTHrP 基因缺失和以细胞特异性方式过度表达将提供有关 PTHrP 在骨发育中作用的相关信息。目标 3 将研究 PTHrP 的核定位信号对 BMSC 和成骨细胞功能的作用。我们在开发用于未来研究的基因工程小鼠方面取得了相当大的进展（参见初步数据）。这些实验的结果将有助于更好地了解 PTHrP 在骨生理学和病理生理学中的作用，以及开发治疗骨疾病的新药物。 环境：兽医生物科学系是一个成功的单位，在内分泌学、免疫学、病毒学、分子生物学和生物化学领域拥有校外资助的研究人员。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员所需的技能提供良好的环境。