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

项目总结 塔玛拉·伊萨科娃，医学博士，MMSc，正在申请K24职业中期研究员奖，以患者为导向 研究(POR)。她是西北大学肾脏病学部的医学副教授 费恩伯格大学医学院。她是内华达州翻译代谢与健康中心的负责人。 公共卫生和医学研究所以及O‘Brien肾核的临床和翻译核心 研究中心。Isakova博士的研究重点是为新的方法开发证据 改善慢性肾脏疾病(CKD)患者的心血管疾病结局。她在以下方面有专长 流行病学研究、POR和多中心临床试验，她曾担任 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 受保护时间1)将更多时间用于指导POR中不同的年轻调查人员群体；2) 通过导师培训和资深导师的指导提高她的POR指导技能；3)扩展到 通过跨学科合作开拓新的科学领域；4)为她的研究项目补充支持 通过新的NIH资金；以及5)增加对临床试验的参与，这将使她能够承担 在协作POR方面处于领先地位。大量证据表明矿物质代谢紊乱是一种 慢性肾脏病心血管疾病发病的机制因素。当前的提案建立了 基于这一科学前提，并扩展了国际和平研究所由R01支持的工作。项目1利用正在进行的工作 在使用粘合剂和烟酰胺的CKD优化管理(联合)试验中，这是一个多中心的试验， 一项随机、双盲、安慰剂对照试验，测试了烟酰胺(阻断有效)的假设 肠道中的磷酸盐转运)和碳酸镧(磷酸盐结合剂)可以安全地降低血清水平 205名患者12个月内磷酸盐和成纤维细胞生长因子(FGF23)水平与安慰剂的比较 在K24的支持下，PI将确定La的疗效 碳酸盐在某些亚基中更为明显，决定了磷酸盐与FGF23的关系 心肌张力降低，并观察干预对心肌下游产物的影响。 烟酰胺和其他代谢物，以及T50上的钙化生物标志物。项目2利用正在进行的 慢性肾功能不全队列研究(CRIC)，这是一项对约4,000名慢性肾功能不全患者的观察性研究 CKD阶段2-4。在K24的支持下，PI将确定是否对T50进行综合评估 和其他中间心血管疾病终点可以帮助识别CKD特异性心血管疾病 疾病表型，她将检查脱氧胆酸可能的可修改决定因素，第二种 胆汁酸参与慢性肾脏病血管钙化的发病机制。实施拟议的目标将 推进心血管疾病非传统危险因素领域，提出潜在治疗建议 PI将在未来的干预研究中测试的方法，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.