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: 7456364
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7456364
• 关键词: Ablation; Academia; Address; Adipocytes; Adult; Affect; Age; Age-Months; American; Animal Model; Apoptosis; Area; Award; Binding; Biochemistry; Biology; Biomedical Research; Birth; Bone Development; Bone Diseases; Bone Marrow; Bone and Cartilage Funding; Calcium; Cell Line; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Chondrocytes; Condition; Data; Development; Doctor of Philosophy; Embryonic Development; Endocrine; Endocrinology; Environment; Equilibrium; Fetus; Functional disorder; Funding; Future; Gene Deletion; Genes; Genetically Engineered Mouse; Goals; Hormone Receptor; Hormones; Human; Hypercalcemia; Hypercalcemia of Malignancy; Immunology; Internal Medicine; Kidney; Knockout Mice; Laboratories; Life; Localized; Malignant Neoplasms; Mammary gland; Mediating; Medicine; Molecular Biology; Morphogenesis; Mus; Muscle relaxation phase; New Agents; Nuclear Localization Signal; Numbers; Ohio; Osteoblasts; Osteoporosis; Paraneoplastic Syndromes; Parathyroid Hormone Receptor; Parathyroid Hormones; Parathyroid gland; Pathology; Physiological; Physiology; Platelet Factor 4; Positioning Attribute; Protein Overexpression; RNA; Regulation; Research; Research Personnel; Role; Scientist; Series; Skeletal Development; Skeletal system; Stromal Cells; System; Technology; Testing; Tissues; Universities; autocrine; bone; career; cell growth; clinical application; college; concept; fetal; human PTH protein; intramembranous bone formation; mutant; novel; paracrine; parathyroid hormone-related protein; professor; programs; receptor; research study; skills; substantia spongiosa; virology

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，博士打算成为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，以支持学术界和生物医学研究的职业。 Ramiro Toribio博士于2001年完成了钙监管博士学位，由美国兽医内科学院（1999）委员会认证，并于2001年加入了托马斯·罗索尔博士的实验室，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）对成骨细胞谱系和成骨细胞功能的承诺的作用。这个概念与医学有关，并且将具有临床应用，因为骨骼质量减少（骨质疏松症）和骨骼脆弱性增加是影响数百万美国人的条件。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体液高钙血症（HHM）的因素。现在已经认识到，PTHRP是具有多种生理功能的内分泌，旁分泌和自分泌因子。 通过与PTH-1受体（PTH1R）结合，PTHRP已显示出在骨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，导致骨骼发育异常。最近的研究还表明，PTHRP对细胞功能的某些影响是由核定位信号介导的。由于有关PTHRP在成骨细胞功能的作用的信息有限，并且我们的实验室致力于研究PTHRP和骨骼生物学的重要方面，因此要测试的总体假设是PTHRP对于BMSC对成骨细胞谱系的承诺很重要，并且对于成骨细胞和osteoblast功能。为了实现这一目标，将进行一系列研究。 AIM 1将通过使用BMSC和PTHRP和PTH1R敲除小鼠以及使用成骨和脂肪细胞系来研究PTHRP对成骨细胞分化和功能的作用。 AIM 2将使用新型动物模型来研究PTHRP对BMSC和成骨细胞功能的功能。 PTHRP基因缺失和以细胞特异性方式过表达将提供有关PTHRP在骨发育中作用的相关信息。 AIM 3将研究PTHRP核定位信号在BMSC和成骨细胞功能上的作用。我们已经取得了长足的进步，以开发用于未来研究的遗传工程小鼠（请参阅初步数据）。这些实验的结果将有助于更好地了解PTHRP在骨骼生理和病理生理学以及创建新药物以治疗骨骼疾病中的作用。 环境：兽医生物科学系是一个成功的单位，该部门在内分泌，免疫学，病毒学，分子生物学和生物化学领域具有外部资助的研究人员。托马斯·罗索尔（Thomas Rosol）博士的实验室将为发展成为成功的独立研究人员所需的技能提供一个绝佳的环境。

项目成果

Deletion of the nuclear localization sequence and C-terminus of parathyroid hormone-related protein decreases osteogenesis and chondrogenesis but increases adipogenesis and myogenesis in murine bone marrow stromal cells.

• DOI: 10.1177/2041731415609298
• 发表时间: 2015-01
• 期刊: Journal of tissue engineering
• 影响因子: 8.2
• 作者: Hildreth BE 3rd;Hernon KM;Dirksen WP;Leong J;Supsavhad W;Boyaka PN;Rosol TJ;Toribio RE
• 通讯作者: Toribio RE