Consequences of Elevated Fibroblast Growth Factor 23 in the Presence and Absence of Kidney Disease

项目摘要 慢性肾脏疾病已成为一种全球性流行病，约有2600万人受到影响 仅在美国。慢性肾脏病（CKD）患者的主要死亡原因/结束 阶段性肾病（ESRD）是由尿毒症性心肌病和中膜血管钙化引起的， 心血管死亡（CVD）。CKD/ESRD中CVD的病因是多因素的，尽管取得了进展， 在治疗相关的合并症时，CKD/ESRD患者的生存率没有显著提高， 提高成纤维细胞生长因子23（FGF 23），一种由骨分泌的磷酸尿激素， CKD早期维持正常磷酸盐血症，并随着CKD进展为ESRD而持续增加， 超生理水平。流行病学研究表明，FGF 23与心血管疾病的发生有关。 CKD/ESRD的死亡率/发病率。然而，关于FGF 23对肿瘤生长的直接影响，存在相互矛盾的数据。 心脏和脉管系统使用动物模型和人类观察研究。因此， 对FGF 23的了解很少，需要确定FGF 23对心血管系统的影响。 系统在肾脏疾病。申请人的实验室已经开发了一种创新的小鼠模型， 肾脏中成纤维细胞生长因子受体（Fgfrs）的复合缺失：肾脏条件性Fgfr 1和 Fgfr 4（KCFgfr 1-/-/Fgfr 4-/-小鼠），其导致FGF 23水平慢性升高而无低磷酸盐血症 这是由于肾对FGF 23的磷酸尿作用的抵抗。申请人的长期目标是确定 FGF 23在健康和肾脏疾病中的作用，特别是在CKD、肾脏疾病和慢性肾脏病的发展/进展方面， 纤维化、炎症、骨矿化和神经认知功能。使用上述鼠标 模型，该提案的总体目标是确定FGF 23对心血管系统的直接影响。 系统在肾脏疾病。我们的初步数据表明，有增加的心脏质量与慢性 暴露于FGF 23与高磷酸盐血症在6个月大，并有增加的主动脉 在12-18月龄小鼠中的钙化。我们将确定FGF 23需要引起的其他因素， 心脏质量增加，因为KCFgfr 1-/-/Fgfr 4-/-小鼠具有中度高磷酸盐血症，如肾脏中所见 疾病我们将使用不同的饮食方案来梳理出FGF 23需要哪些额外的因素， 对心脏有不良影响：高磷酸盐血症、尿毒症毒素或两者兼而有之。与此 研究建议，我们还将研究负责血管平滑肌转化的信号通路。 肌细胞转化为软骨细胞样细胞，促进血管钙化。我们的目标是识别FGFRs 负责促进血管钙化的信号通路。结果是 该提案将为新的治疗靶点提供途径，以减轻FGF 23对心血管的影响 这将对CKD/ESRD患者的心血管死亡率/发病率产生积极影响。

PROJECT SUMMARY Chronic kidney disease has become a worldwide epidemic with approximately 26 million people being affected in the United States alone. The primary cause of death in patients with chronic kidney disease (CKD)/ end stage renal disease (ESRD) is from uremic cardiomyopathy and medial vascular calcification resulting in cardiovascular death (CVD). The etiology of CVD in CKD/ESRD is multifactorial, and despite advances made in treating the associated co-morbidities, the survival of patients with CKD/ESRD has not significantly improved. Fibroblast growth factor 23 (FGF23), a phosphaturic hormone secreted by the bone, is elevated early in CKD to maintain normophosphatemia, and, continues to increase with progression of CKD to ESRD to supraphysiological levels. Epidemiological studies have associated FGF23 with increased cardiovascular mortality/morbidity in CKD/ESRD. However, there is conflicting data regarding the direct effects of FGF23 on the heart and the vasculature using animal models and human observational studies. Thus, the biology of FGF23 is poorly understood and there is a need to determine the effects of FGF23 on the cardiovascular system in kidney disease. The applicant's laboratory has developed an innovative mouse model with a compound deletion of fibroblast growth factor receptors (Fgfrs) in the kidney: Kidney Conditional Fgfr1 and Fgfr4 (KCFgfr1-/-/Fgfr4-/- mice) which results in chronic elevation of FGF23 levels without hypophosphatemia due to renal resistance to the phosphaturic actions of FGF23. The applicant's long term goal is to identify the role of FGF23 in health and kidney disease especially in regards to development/progression of CKD, renal fibrosis, inflammation, bone mineralization, and neurocognitive functions. Using the above described mouse model, the overall objective for this proposal is to identify the direct effects of FGF23 on the cardiovascular system in kidney disease. Our preliminary data indicates that there is increased cardiac mass with chronic exposure to FGF23 together with hyperphosphatemia at 6 months of age and there is increased aortic calcification in 12-18 month old mice. We will determine the additional factors that FGF23 requires to cause increased cardiac mass as KCFgfr1-/-/Fgfr4-/- mice have modest hyperphosphatemia, as seen in kidney disease. We will use different dietary regimens to tease out which additional factors are required for FGF23 to have the adverse effects on the heart: hyperphosphatemia, uremic toxins or a combination of both. With this research proposal, we will also study the signaling pathways responsible for conversion of vascular smooth muscle cells into a chondrocyte-like cells promoting vascular calcification. We aim to identify the Fgfrs responsible for promoting vascular calcification in addition to the signaling pathways. The results from this proposal will offer avenues for new therapeutic targets to mitigate the effects of FGF23 on the cardiovascular system which will have a positive impact on the cardiovascular mortality/morbidity of patients with CKD/ESRD.