Mentored Patient Oriented Research in Mineral Metabolism

描述（由申请方提供）：磷酸盐代谢紊乱，以磷酸盐调节激素、成纤维细胞生长因子23（FGF 23）水平升高为标志，是数百万慢性肾病（CKD）患者心血管疾病和死亡率的新风险因素。高膳食磷酸盐摄入和CKD的存在是FGF 23分泌的主要刺激。在这些情况下，FGF 23水平的逐渐增加是维持正常磷酸盐平衡的适当适应。然而，来自我们团队和其他人的研究表明，FGF 23升高是CKD进展和死亡率更快的一个强大的独立风险因素。作为死亡率增加的一个潜在机制，我们最近证实，升高的FGF 23导致CKD患者左心室肥大的频繁发生。这些数据表明，升高的FGF 23不仅可能代表一种潜在的强大的风险分层生物标志物，而且也是改善CKD结局的新治疗靶点。PI的总体科学生涯目标是通过随机试验证明，基于FGF 23检测或专门针对升高的FGF 23水平的早期干预措施将减缓CKD的进展，减少心血管疾病事件并提高生存率。证明大规模临床试验的合理性需要进一步了解FGF 23生物学，其毒性机制，验证其对流行病学研究结果的影响，这些研究随着时间的推移反复分析FGF 23，以及详细的以患者为导向的研究，以表征候选干预措施对降低FGF 23水平的有效性。在本K24申请的目标1中，我们将对非裔美国人肾脏疾病和高血压研究进行二次分析。我们将通过超声心动图检测FGF 23与心脏结构和功能之间的相关性，我们将检查FGF 23的单次和重复测量作为不良肾脏和心血管结局的新风险因素，我们将使用新兴工具量化FGF 23检测作为CKD风险分层生物标志物的效用。在目标2中，我们将测试饮食磷酸盐限制和磷酸盐结合剂单独和组合作为候选干预措施以降低CKD 3-4期患者中的FGF 23水平的效果。这些研究将成为PI学员的优秀培训工具，并将通过正在进行的翻译研究平行计划进一步加强，PI将在此奖项期间继续培养他的职业发展活动之一。 其他职业发展活动包括领导力的正式课程和在肾脏科实施新的教育倡议，以吸引更多的研究员进行面向患者的研究。 K24将为PI提供至关重要的保护时间和专用资源，以扩大他的导师活动，发展他自己的研究计划，并进一步推进他作为以患者为导向的肾脏病学研究领导者的职业生涯。

DESCRIPTION (provided by applicant): Disordered phosphate metabolism, marked by elevated levels of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is a novel risk factor for cardiovascular disease and mortality in the millions of patients suffering from chronic kidney disease (CKD). High dietary phosphate intake and presence of CKD are major stimuli for FGF23 secretion. In these settings, a progressive increase in FGF23 levels is an appropriate adaptation to maintain normal phosphate balance. However, studies from our team and others demonstrate that elevated FGF23 is a powerful, independent risk factor for more rapid CKD progression and mortality. As a potential mechanism of increased mortality, we recently demonstrated that elevated FGF23 contributes causally to the frequent development of left ventricular hypertrophy in CKD patients. These data suggest that elevated FGF23 may represent not only a potentially powerful risk-stratifying biomarker but also a novel therapeutic target to improve outcomes in CKD. The PI's overarching scientific career goal is to demonstrate by randomized trial that early delivery of interventions based on FGF23 testing, or specifically targeting elevated FGF23 levels, will slow progression of CKD, reduce cardiovascular disease events and improve survival. Justifying a large-scale clinical trial requires further knowledge of FGF23 biology, the mechanisms of its toxicity, validation of its impact on outcomes in epidemiological studies that analyze FGF23 repeatedly over time, and detailed patient-oriented research studies to characterize the efficacy of candidate interventions on reducing FGF23 levels. In Aim 1 of this K24 application, we will perform a secondary analysis of the African American Study of Kidney Disease and Hypertension. We will test the association between FGF23 and cardiac structure and function as determined by echocardiography~ we will examine single and repeated measures of FGF23 as a novel risk factor for adverse renal and cardiovascular outcomes~ and we will use emerging tools to quantify the utility of FGF23 testing as a risk-stratifying biomarker in CKD. In Aim 2, we will tes the effect of dietary phosphate restriction and phosphate binders alone and in combination as candidate interventions to lower FGF23 levels in CKD stage 3-4 patients. These studies will be excellent training vehicles for the PI's trainees and will be further enhanced by an ongoing parallel program in translational research that the PI will continue to cultivate as one of his career development activities during this award. Other career development activities include formal coursework in leadership and the implementation of a new educational initiative in the Division of Nephrology to attract additional fellows to patient-oriented research. The K24 will provide the PI with critically important protected time and dedicated resources to expand his mentorship activities, grow his own research program and further advance his career as a leader in patient-oriented research in nephrology.