Sclerostin Regulation of Skeletal Mineralization and Phosphate Metabolism

硬化素对骨骼矿化和磷酸盐代谢的调节

基本信息

批准号：
10457434
负责人：
Ryan Dee Ross
金额：
$ 8.7万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457434
关键词：
Adolescent Adult Animal Model Antibodies Biochemical Bone Matrix Calcitriol Cell Culture Techniques Cell Line Cellular biology Clinical Pathology Data Defect Disease Endocrinology Endopeptidases Excretory function Familial hypophosphatemic bone disease Funding Gene Expression Gene Proteins Genes Genetic Goals Heritability Homologous Gene Hormones Hypophosphatemia In Vitro Inorganic Phosphate Transporter Kidney Kinetics Laboratory Research Lead Link Mentors Metabolism Minerals Modeling Molecular Molecular Biology Mus Mutation Osteocytes Osteogenesis Osteomalacia Osteoporosis Pathologic Pathway Analysis Pathway interactions Patients Pharmacologic Substance Physiologic calcification Production Proteins Publications Publishing Regulation Reporting Research Research Personnel Residual state Rickets Role Serum Skeletal Development Suggestion Techniques Testing Training Transgenic Animals Translational Research Vitamin D WNT Signaling Pathway base beta catenin bone bone mass bone strength conditional knockout fibroblast growth factor 23 in vivo in vivo Model inhibitor inorganic phosphate interest mRNA Expression mineralization mouse model novel novel therapeutics overexpression pre-clinical promoter response skeletal tool treatment strategy urinary

项目摘要

Project Summary X-linked hypophosphatemia (XLH) is the most common form of heritable Rickets. Patients with XLH present with two related clinical pathologies; defective bone matrix mineralization and hypophosphatemia. The mineralization defect is primarily caused by the accumulation of mineralization inhibitors within the bone matrix, while hypophosphatemia is attributed to increased circulating levels of the phosphate-regulating hormone, fibroblast growth factor 23 (FGF23). Although the mutation that causes XLH has been identified as the phosphate-regulating endopeptidase homologue, X-linked (PHEX) gene, the factors that ultimately lead to poor mineralization and elevated FGF23 are not well described. My preliminary data implicates the protein sclerostin in both skeletal mineralization and phosphate metabolism regulation. The current proposal will test the hypothesis that sclerostin is a key regulator of skeletal mineralization and phosphate metabolism using both mechanistic and translational research aims. Aim 1 will investigate potential mechanisms of action using both in vitro and in vivo models while Aim 2 will test the use of Scl-Ab as a treatment option for XLH using the Hyp mouse model of XLH. My long-term goal is to become a leading independent researcher in the field of skeletal mineralization and mineral metabolism. In order to achieve these goals, I have chosen successful researchers to serve as mentors, including Dr. Anne George (primary mentor), an expert in skeletal mineralization, and Dr. Di Chen (co-mentor), an expert in skeletal development and Wnt signaling. The research described will serve as an ideal training vehicle for me to develop expertise in the use of cell culture and transgenic animal models, while also furthering my understanding of the systemic control of mineral metabolism. The training plan will focus on cell and molecular biology, endocrinology and the systemic control of mineral metabolism, and advanced training in grantsmanship, which will give me the tools necessary to build a successful independent research laboratory.

项目摘要 X连锁低磷血症（XLH）是可遗传的rick鼠的最常见形式。 XLH患者存在具有两个相关的临床病理；有缺陷的骨基质矿化和下磷酸血症。这矿化缺陷主要是由矿化抑制剂在骨基质中的积累引起的，低磷酸血症归因于磷酸激素的循环水平升高，但成纤维细胞生长因子23（FGF23）。尽管引起XLH的突变已被确定为磷酸盐调节的内肽酶同源物，X连锁（pHEx）基因，这些因素最终导致较差矿化和FGF23的升高尚未很好地描述。我的初步数据暗示蛋白质硬化蛋白在骨骼矿化和磷酸盐代谢调节中。当前的建议将测试假设硬化症是骨骼矿化和磷酸代谢的关键调节剂机械和翻译研究的目的。 AIM 1将使用两者都调查动作的潜在机制 AIM 2的体外和体内模型将测试使用SCL-AB作为XLH的治疗选择 XLH的鼠标模型。我的长期目标是成为骨骼领域的领先独立研究人员矿物质和矿物质代谢。为了实现这些目标，我选择了成功的研究人员担任指导者，包括骨骼矿化专家Anne George（主要导师）和博士 Di Chen（Co-Centor），骨骼发育和WNT信号的专家。描述的研究将服务作为我的理想训练工具，是我在使用细胞培养和转基因动物模型方面发展专业知识的理想训练工具，同时还进一步了解了对矿物质代谢的系统控制。培训计划将专注于细胞和分子生物学，内分泌学和矿物质代谢的全身控制以及授予技巧的高级培训将为我提供建立成功独立的必要工具研究实验室。