Mentored Patient Oriented Research in Mineral Metabolism

指导以患者为导向的矿物质代谢研究

基本信息

批准号：
9385039
负责人：
MYLES S WOLF
金额：
$ 15.65万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9385039
关键词：
African American Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Award Biological Markers Biology Blood Pressure Cardiac Cardiovascular Diseases Cardiovascular system Caring Categories Caucasians Cessation of life Chronic Kidney Failure Chronic Kidney Insufficiency Clinical Clinical Data Clinical Trials Cohort Studies Creatinine Data Databases Development Diagnostic Diet Disease Disease Outcome Disease Progression Early treatment Echocardiography End stage renal failure Epidemic Epidemiologic Studies Equilibrium Event Exhibits Functional disorder Future Goals Heart failure Hormones Hospitalization Hypertension Image Incidence Intake Intervention Kidney Kidney Diseases Knowledge Leadership Left Ventricular Hypertrophy Left Ventricular Mass Measurement Measures Mentors Mentorship Metabolism Methodology Minerals Myocardial Infarction National Institute of Diabetes and Digestive and Kidney Diseases Nephrology Nephrosclerosis Outcome Participant Patients Pharmaceutical Preparations Phase Placebos Population Proteinuria Public Health Randomized Reporting Research Resources Risk Risk Factors Sampling Serum Smoking Staging Stimulus Stroke Structure Testing Therapeutic Therapeutic Studies Thick Time Tissues Toxic effect Training Translational Research Ursidae Family Validation absorption adverse outcome animal data base blood pressure regulation cardiovascular disorder risk career career development clinical practice cohort design fibroblast growth factor 23 follow-up high risk human data improved improved outcome indexing inorganic phosphate mortality new therapeutic target novel novel strategies novel therapeutics patient oriented research programs randomized trial research study response therapeutic target tool

项目摘要

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.

描述（申请人提供）：磷酸盐代谢无序的代谢，以调节激素的磷酸盐水平升高，成纤维细胞生长因子23（FGF23），是数百万患有慢性肾脏病（CKD）的数百万患者的心血管疾病和死亡率的新风险因素。高饮食磷酸盐摄入量和CKD的存在是FGF23分泌的主要刺激。在这些情况下，FGF23水平逐渐增加是维持正常磷酸盐平衡的适当适应性。但是，我们团队和其他人的研究表明，升高的FGF23是CKD进展和死亡率更快的强大，独立的风险因素。作为增加死亡率的潜在机制，我们最近证明，FGF23升高为CKD患者的左心室肥大频繁发展而有因果关系。这些数据表明，升高的FGF23不仅可以代表潜在的强大风险分离生物标志物，而且还代表了改善CKD预后的新型治疗靶标。 PI的总体科学职业目标是通过随机试验证明，基于FGF23测试或专门针对FGF23水平升高的干预措施的早期提供，将减缓CKD的进展，减少心血管疾病事件并提高生存率。证明一项大规模临床试验的合理性需要进一步了解FGF23生物学，其毒性的机制，验证其对流行病学研究中的影响的影响，这些研究随着时间的推移反复分析FGF23，以及详细的以患者为导向的研究，以表征降低FGFF23级别的候选干预措施。在此K24应用的AIM 1中，我们将对非裔美国人对肾脏疾病和高血压研究进行二次分析。我们将测试通过超声心动图确定的FGF23与心脏结构与功能之间的关联〜我们将研究FGF23的单一和重复测量，是不良肾脏和心血管结果的新型风险因素〜，我们将使用新兴工具来量化FGF23测试的效用，以将FGF23测试作为一种风险 - cks-Stratifying Biomarkarkerarearseraremark in ckd in ckd in ckd。在AIM 2中，我们将单独使用饮食磷酸盐限制和磷酸盐结合剂的影响，并将其作为候选干预措施在CKD阶段3-4患者中降低FGF23水平的效果。这些研究将是PI的受训者的出色训练车辆，并通过转化研究中正在进行的并行计划进一步增强，PI将继续培养为他在该奖项期间的职业发展活动之一。其他职业发展活动包括领导领域的正式课程以及在肾脏病科学划分的新教育计划中实施，以吸引其他研究员进入以患者为导向的研究。 K24将为PI提供至关重要的保护时间和专门的资源，以扩大他的指导活动，发展自己的研究计划，并进一步促进他作为肾脏病患者研究的领导者的职业。