FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS

描述(由申请人提供)：血清磷浓度的调节是一个复杂的过程，我们目前的模型还远远不完整。我们从染色体12p13.3中克隆了一个新的基因，FGF23，它编码一种分泌因子，并证明当该基因突变时，该基因与肾性磷酸消耗障碍常染色体显性遗传性低磷血症性软骨病(ADHR)有关。我们还确定了在导致致癌性低磷血症性骨软化症(OHO)的肿瘤中，成纤维细胞生长因子-23过表达，体内证据支持成纤维细胞生长因子-23作为一种磷尿性物质的作用。然而，目前还不清楚成纤维细胞生长因子-23导致孤立的肾脏磷酸盐消耗的细胞和分子机制。本研究的长期目标是了解调控肾磷酸盐重吸收的基因的分子生理学和功能，这些基因由成纤维细胞生长因子-23控制。对磷酸盐消耗代谢综合征ADHR和OHO的研究，为发现控制肾脏磷酸盐稳态的新途径提供了独特的机会。目前还没有ADHR的动物模型，因此限制了测试关于疾病潜在生理机制的假说的能力。在这项建议中要检验的假设是：成纤维细胞生长因子-23通过一种特定的受体作用，导致肾脏近端小管基因转录和翻译的变化，从而导致肾脏对磷的吸收减少。我们将通过以下具体目标来验证这一假说：(1)测试在体内可能受成纤维细胞生长因子-23调控的小鼠肾脏和骨骼基因表达的变化；(2)确定参与成纤维细胞生长因子-23对肾脏近端小管作用的成纤维细胞生长因子受体(S)；以及(3)建立合适的ADHR小鼠模型并了解该疾病的表现。建议的研究结果将为ADHR和OHO的发病机制提供洞察力，并有助于更好地理解长期决定磷酸盐稳态的机制。

DESCRIPTION (provided by applicant): The regulation of serum phosphate concentrations is a complex process and our current models are far from complete. We positionally cloned a novel gene from chromosome 12p13.3, FGF23, that encodes a secreted factor, and demonstrated that, when mutated, the gene is responsible for the renal phosphate wasting disorder autosomal dominant hypophosphatemic rickets (ADHR). We also determined that FGF-23 is overexpressed in tumors causing oncogenic hypophosphatemic osteomalacia (OHO), and in vivo evidence supports the role of FGF-23 as a phosphaturic substance. The cellular and molecular mechanisms by which FGF-23 causes isolated renal phosphate wasting are currently unknown, however. The long-term goals of the present studies are to understand the molecular physiology and function of genes involved in regulating renal phosphate reabsorption controlled by FGF-23. The study of the phosphate-wasting metabolic syndromes, ADHR and OHO, provides a unique opportunity to discover novel pathways controlling renal phosphate homeostasis. Currently there are no animal models for ADHR, thus limiting the ability to test hypotheses regarding the physiological mechanisms underlying the disease. The hypothesis to be tested within this proposal is: FGF-23 acts through a specific receptor to cause changes in gene transcription and translation in kidney proximal tubule that result in decreased renal absorption of phosphorous. We will test this hypothesis through the following Specific Aims: (1) to test for changes in the expression of renal and skeletal genes in mice that may be regulated by FGF-23 in vivo; (2) to determine the FGF receptor(s) involved in FGF-23 actions on the kidney proximal tubule; and (3) to develop an appropriate mouse model of ADHR and to understand the manifestations of the disorder. The results of the proposed studies will provide insight into the pathogenesis of ADHR and OHO, as well as lead to improved understanding of the mechanisms dictating phosphate homeostasis in the long-term.