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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）是遗传性佝偻病最常见的形式。存在XLH的患者有两种相关的临床病理;骨基质矿化缺陷和低磷血症。的矿化缺陷主要由骨基质内矿化抑制剂的积累引起，虽然低磷酸盐血症归因于磷酸盐调节激素的循环水平增加，成纤维细胞生长因子23（FGF 23）。虽然导致XLH的突变已被确定为磷酸调节内肽酶同源物，X连锁（PHEX）基因，最终导致穷人的因素，矿化和升高的FGF 23没有很好地描述。我的初步数据显示硬化蛋白在骨骼矿化和磷酸盐代谢调节中的作用。目前的提案将测试假设硬化蛋白是骨骼矿化和磷酸盐代谢的关键调节剂，机械论和转化研究的目的。目的1将研究潜在的作用机制，体外和体内模型，而Aim 2将使用Hyp检测Scl-Ab作为XLH的治疗选择， XLH小鼠模型。我的长期目标是成为骨骼领域领先的独立研究人员矿化和矿物质代谢。为了实现这些目标，我选择了成功的研究人员担任导师，包括安妮乔治博士（主要导师），骨骼矿化专家，和博士。 Di Chen（共同导师），骨骼发育和Wnt信号传导专家。所描述的研究将服务于作为一个理想的培训工具，我发展的专业知识，在使用细胞培养和转基因动物模型，同时也加深了我对矿物质代谢系统控制的理解。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系统控制，高级培训，这将给我必要的工具，建立一个成功的独立研究实验室。