FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS

描述（由申请人提供）：血清磷酸盐浓度的调节是一个复杂的过程，我们目前的模型还远远不够完整。我们从12p13.3染色体上克隆了一个编码分泌因子的新基因FGF23，并证明，当突变时，该基因与肾磷酸盐消耗障碍常染色体显性低磷血症佝偻病（ADHR）有关。我们还确定了FGF-23在引起癌性低磷性骨软化症（OHO）的肿瘤中过度表达，并且体内证据支持FGF-23作为一种磷酸化物质的作用。然而，目前尚不清楚FGF-23引起孤立肾磷酸盐消耗的细胞和分子机制。本研究的长期目标是了解FGF-23控制的肾脏磷酸盐重吸收调控基因的分子生理学和功能。磷酸盐消耗代谢综合征，ADHR和OHO的研究，提供了一个独特的机会，发现控制肾脏磷酸盐稳态的新途径。目前还没有ADHR的动物模型，因此限制了测试关于该疾病潜在生理机制的假设的能力。本提案需要验证的假设是：FGF-23通过特定受体作用，引起肾近端小管基因转录和翻译的改变，从而导致肾对磷的吸收减少。我们将通过以下具体目的来验证这一假设：(1)测试体内可能受FGF-23调节的小鼠肾脏和骨骼基因表达的变化；(2)确定参与FGF-23作用于肾近端小管的FGF受体；(3)建立合适的ADHR小鼠模型，了解该疾病的表现。拟议研究的结果将为ADHR和OHO的发病机制提供深入的见解，并提高对长期决定磷酸盐稳态的机制的理解。

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.