GAT FGF23 and Vascular Calcification

 描述(申请人提供)：FGF23和血管钙化摘要慢性肾脏疾病(CKD)和终末期肾脏疾病(ESRD)患者的寿命缩短，心血管疾病是这些患者的主要死亡原因。血管钙化在CKD和ESRD患者中非常普遍，被注意到发生在早期，是心血管预后的强烈预测因素。血管钙化的危险因素包括高磷血症、尿毒症和钙磷产物增加，但CKD患者在这些明显的生化异常发展之前就出现了血管钙化。最近的临床研究表明，CKD/ESRD患者的血管钙化与成纤维细胞生长因子23(FGF23)水平升高有关。到目前为止，研究FGF23在体内血管钙化中的作用一直是一个充满问题的问题。理想的体内动物模型应该是血磷水平、血钙水平或肾功能无明显变化，但FGF23水平升高的动物模型，以便研究FGF23对血管钙化的独立作用。我们现在已经开发出这样一个理想的小鼠模型：FGFR1-/-/FGFR4-/-小鼠。该模型包括肾脏成纤维细胞生长因子受体1(FGFR1)的条件性缺失和成纤维细胞生长因子受体4(FGFR4)的整体缺失。FGFR1-/-/FGFR4-/-小鼠FGF23水平升高，肾功能正常，血钙水平正常，无低磷血症。FGFR4在我们研究的血管钙化的小鼠主动脉中不正常表达。因此，FGFR4在FGFR1-/-/FGFR4-/-小鼠体内的整体缺失不会对研究FGF23对主动脉钙化的影响产生任何影响。我们计划利用野生型和高磷血症或尿毒症状态下的FGFR1-/-/FGFR4-/-小鼠研究FGF23在血管钙化中的作用。我们能够在仅改变饮食的情况下，在两组小鼠保持正常肾功能的同时，达到所需的和可比较的血清磷水平。此外，为了了解尿毒症毒素和FGF23在血管钙化中的共同作用，我们将通过饮食中腺嘌呤诱导CKD状态。如果这项拨款中建议的实验证实了我们的假设，这项工作将对确定FGF23在CKD/ESRD患者的血管系统中的独立作用以及相关的心血管发病率和死亡率产生重大影响。最终，了解FGF23在血管钙化中的作用将允许靶向治疗来改善这一过程，这反过来将对提高CKD/ESRD患者的存活率产生巨大影响。

 DESCRIPTION (provided by applicant): FGF23 and Vascular Calcification ABSTRACT Patients with chronic kidney disease (CKD) and end stage renal disease (ESRD) have a shortened life span and cardiovascular disease is the leading cause of death in these patients. Vascular calcification is highly prevalent in patients with CKD and ESRD, is noted to occur at an early age, and is a strong predictor of cardiovascular outcome. Risk factors for vascular calcification include hyperphosphatemia, uremia and increased calcium phosphate product but patients with CKD develop vascular calcification prior to the development of these overt biochemical abnormalities. Recent clinical studies have demonstrated an association between vascular calcification and elevated fibroblast growth factor 23 (FGF23) levels in patients with CKD/ESRD. To study the role of FGF23 in vascular calcification in vivo has been fraught with problems until now. An ideal in vivo model would be an animal model with no major disturbances in serum phosphate levels, serum calcium levels or renal function but have elevated FGF23 levels so that the independent effects of FGF23 on vascular calcification can be studied. We have now developed such an ideal mouse model; Fgfr1-/-/Fgfr4-/- mice. This model involves a kidney conditional deletion of fibroblast growth factor receptor 1 (Fgfr1) and a global deletion of fibroblast growth factor receptor 4 (Fgfr4). Fgfr1-/-/Fgfr4-/- mice have ~50 fol elevated FGF23 levels, normal renal function and serum calcium levels and lack hypophosphatemia. Fgfr4 is not normally expressed in mouse aorta, the subject of vascular calcification in our study. Therefore, global deletion of Fgfr4 in our Fgfr1-/-/Fgfr4-/- mice will have no effect on studying the effects of FGF23 on aortic calcification. We plan to study the role of FGF23 in vascular calcification using wild type and Fgfr1-/-/Fgfr4-/- mice in states of hyperphosphatemia or uremia. We are able to achieve desired and comparable serum phosphorus levels while maintaining normal renal function in both groups of mice with dietary alteration alone. Additionally, to understand the role of uremic toxins and FGF23 together on vascular calcification, we will induce a CKD state with dietary adenine. If the proposed experiments in this grant confirm our hypothesis, this work would have a great impact on defining the independent role of FGF23 on the vasculature and the associated cardiovascular morbidity and mortality in patients with CKD/ESRD. Ultimately, understanding the role of FGF23 in vascular calcification will allow for targeted therapy to ameliorate this process which in turn will have a huge impact on improving survival of patients with CKD/ESRD.