Mentored patient-oriented research of novel mechanisms for cardiovascular disease in patients with chronic kidney disease

项目摘要 Tamara Isakova，MD，MMSC正在申请K24中期职业研究者奖，以患者为导向 研究（POR）。她是西北大学肾脏病学系的医学副教授， 范伯格大学医学院。她指导翻译代谢和健康中心， 公共卫生和医学研究所以及奥布莱恩肾脏中心的临床和转化中心 研究中心Isakova博士的研究重点是开发新方法的证据， 改善慢性肾病（CKD）患者心血管疾病结局。她擅长于 流行病学研究，POR和多中心临床试验，她曾担任科学导师， 医学生、住院医生、研究员和初级教员。来自K24的支持将为Isakova博士提供 保护时间1）投入更多的时间来指导POR中的各种年轻调查人员; 2） 通过导师培训和高级导师的指导，提高她的POR指导技能; 3）扩展到 通过跨学科合作的新科学领域; 4）补充对她的研究计划的支持 通过新的NIH资助;以及5）增加对临床试验的参与，这将使她能够承担 领导力的合作。大量的证据表明，矿物质代谢紊乱是一种 CKD心血管疾病发病机制的机制贡献者。目前的建议是建立 基于这一科学前提，并扩展了PI的R 01支持的工作。项目1利用正在进行的工作 在多中心的CKD结合剂和烟酰胺优化管理（联合收割机）试验中， 一项随机、双盲、安慰剂对照试验，检验了烟酰胺（阻断活性 磷酸盐转运）和碳酸镧（磷酸盐结合剂）将安全地降低血清 205例患者在12个月内与安慰剂相比的磷酸盐和成纤维细胞生长因子（FGF 23）水平 CKD 3b-4期。在K24的支持下，PI将确定镧的疗效是否 碳酸盐在某些亚组中更明显，确定磷酸盐和FGF 23的关系 降低心肌应变，并研究干预措施对下游产品的影响， 烟酰胺和其他代谢物以及钙化生物标志物T50。项目2利用正在进行的工作， 慢性肾功能不全队列研究（CRIC），这是一项对约4，000例患者进行的观察性研究， CKD 2 - 4期。在K24的支持下，PI将确定T50的综合评估是否 和其他中间心血管疾病终点可以帮助确定CKD特异性心血管疾病 疾病表型，她将检查脱氧胆酸，一个次要的 胆汁酸参与CKD血管钙化的发病机制。拟议目标的实施将 推进心血管疾病的非传统危险因素领域，提出潜在的治疗方法， PI将在未来的干预研究中测试这些方法，并将为POR培训提供肥沃的土壤。

PROJECT SUMMARY Tamara Isakova, MD, MMSc is applying for the K24 Midcareer Investigator Award in Patient-Oriented Research (POR). She is an Associate Professor of Medicine in the Division of Nephrology at the Northwestern University Feinberg School of Medicine. She directs the Center for Translational Metabolism and Health within the Institute for Public Health and Medicine and the Clinical and Translational Core of the O'Brien Kidney Core Research Center. Dr. Isakova's research is focused on developing the evidence for novel approaches to improve cardiovascular disease outcomes in patients with chronic kidney disease (CKD). She has expertise in epidemiologic studies, POR and multi-center clinical trials, and she has served as a scientific mentor for medical students, residents, fellows, and junior faculty. Support from the K24 will provide Dr. Isakova with protected time 1) to devote more time to mentoring a diverse group of young investigators in POR; 2) to improve her POR mentoring skills through mentor training and guidance from senior mentors; 3) to expand into new scientific areas through cross-disciplinary collaborations; 4) to replenish support for her research program through new NIH funding; and 5) to increase involvement in clinical trials, which will allow her to assume leadership in collaborative POR. A large body of evidence implicates disordered mineral metabolism as a mechanistic contributor to the pathogenesis of cardiovascular disease in CKD. The current proposal builds upon this scientific premise and extends the R01-supported work of the PI. Project 1 leverages ongoing work in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial, which is a multi-center, randomized, double-blinded, placebo-controlled trial that tested the hypothesis that nicotinamide (blocks active phosphate transport in the gut) and lanthanum carbonate (phosphate binder) would safely lower serum phosphate and fibroblast growth factor (FGF23) levels compared to placebo over 12 months in 205 patients with CKD stages 3b–4. With support from the K24, the PI will ascertain whether the efficacy of lanthanum carbonate was more pronounced in certain subgroups, determine the relationship of phosphate and FGF23 lowering with myocardial strain, and investigate the effects of interventions on downstream products of nicotinamide and other metabolites and on T50, a calcification biomarker. Project 2 leverages ongoing work in the Chronic Renal Insufficiency Cohort (CRIC) Study, which is an observational study of ~4,000 patients with CKD stages 2 – 4. With support from the K24, the PI will determine whether a combined assessment of T50 and other intermediate cardiovascular disease end-points could help identify a CKD-specific cardiovascular disease phenotype, and she will examine possible modifiable determinants of deoxycholic acid, a secondary bile acid implicated in the pathogenesis of vascular calcification in CKD. Conduct of the proposed Aims will advance the field of non-traditional risk factors for cardiovascular disease, suggest potential therapeutic approaches that the PI will test in future interventional studies and will provide a fertile ground for POR training.