GAT FGF23 and Vascular Calcification

 描述（申请人提供）：FGF 23和血管钙化摘要慢性肾病（CKD）和终末期肾病（ESRD）患者的寿命缩短，心血管疾病是这些患者死亡的主要原因。血管钙化在慢性肾病和终末期肾病患者中非常普遍，通常发生在早期，并且是心血管结局的强有力预测因素。血管钙化的风险因素包括高磷酸盐血症、尿毒症和磷酸钙产物增加，但CKD患者在发生这些明显的生化异常之前发生血管钙化。最近的临床研究表明，CKD/ESRD患者血管钙化与成纤维细胞生长因子23（FGF 23）水平升高之间存在相关性。迄今为止，研究FGF 23在体内血管钙化中的作用一直充满问题。理想的体内模型将是血清磷酸盐水平、血清钙水平或肾功能没有重大干扰但具有升高的FGF 23水平的动物模型，使得可以研究FGF 23对血管钙化的独立作用。我们现在已经开发了这样一种理想的小鼠模型; Fgfr 1-/-/Fgfr 4-/-小鼠。该模型涉及成纤维细胞生长因子受体1（Fgfr 1）的肾脏条件性缺失和成纤维细胞生长因子受体4（Fgfr 4）的整体缺失。Fgfr 1-/-/Fgfr 4-/-小鼠具有约50 fol升高的FGF 23水平、正常的肾功能和血清钙水平并且没有低磷酸盐血症。fgfr 4在我们研究中血管钙化的小鼠主动脉中不正常表达。因此，在我们的Fgfr 1-/-/Fgfr 4-/-小鼠中Fgfr 4的整体缺失将对研究FGF 23对主动脉钙化的作用没有影响。我们计划使用处于高磷血症或尿毒症状态的野生型和Fgfr 1-/-/Fgfr 4-/-小鼠研究FGF 23在血管钙化中的作用。我们能够达到所需的和可比的血清磷水平，同时保持正常的肾功能，在两组小鼠的饮食改变单独。此外，为了了解尿毒症毒素和FGF 23在血管钙化中的作用，我们将用饮食腺嘌呤诱导CKD状态。如果这项研究中的实验证实了我们的假设，这项工作将对确定FGF 23对血管系统的独立作用以及CKD/ESRD患者相关的心血管发病率和死亡率产生重大影响。最终，了解FGF 23在血管钙化中的作用将允许靶向治疗来改善这一过程，这反过来将对改善CKD/ESRD患者的生存率产生巨大影响。

 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.