Pathogenesis of XLH/Hyp: Role of Phex MEPE and FGF23

XLH/Hyp 的发病机制：Phex MEPE 和 FGF23 的作用

• 批准号: 7436126
• 负责人: L DARRYL QUARLES
• 金额: $ 30.05万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-05 至 2009-07-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7436126
• 关键词: Accounting; Cell surface; Data; Defect; Disease; Enzymes; Extracellular Matrix; Extracellular Matrix Proteins; Familial hypophosphatemic bone disease; Genetic; Growth Factor; Growth Factor Receptors; Homeostasis; Homologous Gene; Hormones; Hypophosphatemia; Inherited; Investigation; Kidney; Link; Mediating; Membrane; Metabolism; Metalloproteases; Modeling; Molecular; Mus; Mutation; Oligopeptides; Oncogenic; Osteomalacia; Pathogenesis; Phage Display; Phenotype; Play; Proteins; Rickets; Role; Screening procedure; Skeletal system; Vitamin D; Yeasts; base; bone; inhibitor/antagonist; inorganic phosphate; mineralization; novel; receptor; response; tumor; wasting; yeast two hybrid system

DESCRIPTION (provided by applicant): There is evidence for a hormone/enzyme/extracellular matrix protein cascade for maintaining systemic phosphate homeostasis and mineralization. Genetic studies of Autosomal Dominant Hypophosphatemic Rickets (ADHR) and X-linked hypophosphatemia (XLH) identified the phosphaturic hormone FGF23 and the membrane metalloprotease PHEX, while investigations of Tumor Induced Osteomalacia (TIO) discovered the extracellular matrix protein MEPE. Similarities between ADHR, XLH, and TIO provide the basis for a compelling model to explain the common pathogenesis of renal phosphate wasting and defective mineralization in these disorders. In this model, circulating phosphaturic hormone, FGF23, and local inhibitor(s) of mineralization, MEPE, respectively cause renal phosphate wasting and intrinsic mineralization abnormalities. We have data that XLH is caused by inactivating mutations of Phex that leads to altered activity of unidentified oligopeptide substrates that secondarily modify the expression and/or degradation of the phosphaturic factor FGF23 and the mineralization inhibitor MEPE. In Aim 1 we will use mouse genetic approaches to establish a cause-and-effect relationship between increased FGF23 and hypophosphatemia in Phex-deficient Hyp mouse homologue of XLH. In these studies, Phex-deficient Hyp mice will be transferred onto FGF23 null background to attempt rescue of the Hyp phenotype. We will also explore the molecular mechanisms whereby FGF23 regulates renal phosphate handling and skeletal mineralization by examining the effects of FGF23 administration in mice lacking specific fibroblastic growth factor receptors. In Aim 2, we will investigate the role that MEPE plays in the apparent intrinsic mineralization defect by transferring Phex-deficiency onto the MEPE null background. Finally, in Aim 3 we will use complementary phage display and yeast-two hybrid screening to identify physiologically relevant Phex substrates, inhibitors and/or interacting proteins that allow this enzyme to control FGF23 and MEPE metabolism.

描述(由申请人提供)：有证据表明，激素/酶/细胞外基质蛋白级联能维持全身磷酸盐的稳态和矿化。常染色体显性遗传性低磷血症(ADHR)和X连锁低磷血症(XLH)的遗传学研究发现了磷酸尿激素FGF23和膜金属蛋白酶PHEX，而肿瘤诱导的骨软化症(TO)则发现了细胞外基质蛋白MEPE。ADHR、XLH和TIO之间的相似性提供了一个令人信服的模型的基础，以解释这些疾病中肾脏磷酸盐消耗和矿化缺陷的常见发病机制。在该模型中，循环磷尿酸激素、成纤维细胞生长因子23和局部矿化抑制物(S)分别导致肾脏磷酸盐消耗和内源性矿化异常。我们有数据表明，XLH是由PHEX的失活突变引起的，该突变导致未知寡肽底物的活性改变，从而继而改变磷酸尿酸因子FGF23和矿化抑制剂MEPE的表达和/或降解。在目标1中，我们将使用小鼠遗传学方法来建立FGF23增加和低磷血症之间的因果关系，在PHEX缺陷的Hyp小鼠中XLH同源物。在这些研究中，PHEX缺陷的Hyp小鼠将被转移到FGF23缺失的背景上，试图挽救Hyp表型。我们还将通过检测FGF23对缺乏成纤维细胞生长因子受体的小鼠的影响，探索FGF23调节肾脏磷酸盐转运和骨骼矿化的分子机制。在目标2中，我们将通过将PHEX缺乏转移到MEPE零背景来研究MEPE在明显的内在矿化缺陷中所起的作用。最后，在目标3中，我们将使用互补噬菌体展示和酵母双杂交筛选来鉴定生理上相关的PHEX底物、抑制物和/或相互作用蛋白，使该酶能够控制FGF23和MEPE的代谢。