FGF-23 REGULATION OF PHOSPHATE HOMEOSTASIS

超出所提供的空间。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未完成。我们从染色体12p13.3定位克隆了一个新的基因，FGF 23，它编码一种分泌因子，并证明，当突变时，该基因是负责肾磷酸盐消耗性疾病常染色体显性低磷酸盐血症佝偻病（ADHR）。我们还确定FGF-23在肿瘤中过度表达，导致致癌性低磷酸盐血症性骨软化症（OHO），体内证据支持FGF-23作为磷酸盐尿物质的作用。然而，FGF-23引起孤立性肾磷酸盐消耗的细胞和分子机制目前尚不清楚。本研究的长期目标是了解FGF-23调控肾磷酸盐重吸收的分子生理学和基因功能。对磷酸盐消耗代谢综合征、ADHR和OHO的研究为发现控制肾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，因此限制了测试有关疾病生理机制的假设的能力。本提案中待检验的假设是：FGF-23通过特异性受体起作用，引起肾近端小管中基因转录和翻译的变化，导致肾磷吸收减少。我们将通过以下具体的施舍来检验这一假设：1.测试小鼠中肾脏和骨骼基因表达的变化，其可在体内由FGF-23调节; 2.）以确定参与FGF-23对肾近端小管作用的FGF受体;和3.）建立一个合适的ADHR小鼠模型，并了解该疾病的表现。拟议研究的结果将提供深入了解ADHR和OHO的发病机制，以及导致更好地了解长期支配磷酸盐稳态的机制。性能现场=

EXCEED THE SPACE PROVIDED. 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 over expressed 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 alms: 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. PERFORMANCE SITE ========================================Section End===========================================