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

指导以患者为中心的慢性肾病患者心血管疾病新机制的研究

• 批准号: 10386759
• 负责人: Tamara Isakova
• 金额: $ 11.63万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386759
• 关键词: Address; Adverse event; Ancillary Study; Animals; Area; Arrhythmia; Atrial Fibrillation; Bile Acids; Biological Markers; Calcitriol; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Trials; Cohort Studies; Collaborations; Complication; Consequentialism; Data; Deoxycholic Acid; Development; Diagnostic tests; Diet; Dietary Component; Disease; Disease Outcome; Evaluation; Event; Excretory function; Faculty; Fatty acid glycerol esters; Fibroblast Growth Factor; Food; Frequencies; Funding; Future; Health; Heart failure; Homeostasis; Image; Individual; Institutes; Intake; Intervention; Intervention Studies; Investigation; Kidney; Knowledge; Laboratories; Leadership; Left Ventricular Hypertrophy; Left Ventricular Mass; Left ventricular structure; Magnetic Resonance Imaging; Measurement; Measures; Medial; Medical Students; Medicine; Mentors; Metabolism; Midcareer Investigator Award in Patient-Oriented Research; Minerals; Modeling; Multi-Institutional Clinical Trial; Myocardial; Nephrology; Niacinamide; Observational Study; PTH gene; Pathogenesis; Patient Care; Patients; Physiologic pulse; Placebos; Plasma; Production; Proteins; Public Health; Questionnaires; Randomized; Research; Research Infrastructure; Research Personnel; Research Support; Research Training; Risk; Risk Factors; Sampling; Series; Serum; Smooth Muscle Myocytes; Sodium; Subgroup; Testing; Therapeutic; Time; Training; United States National Institutes of Health; Universities; Vascular Smooth Muscle; Vascular calcification; Work; absorption; adjudicate; base; calcification; calcium phosphate; cardiac magnetic resonance imaging; cardiovascular risk factor; clinical care; clinical investigation; cohort; coronary artery calcification; design; diagnostic tool; dietary; disease phenotype; double-blind placebo controlled trial; endoplasmic reticulum stress; epidemiology study; experimental study; fibroblast growth factor 23; follow-up; gut dysbiosis; high risk population; improved; improved outcome; indexing; inorganic phosphate; intervention effect; lanthanum carbonate; medical schools; mid-career faculty; mortality; mortality risk; novel; novel diagnostics; novel strategies; patient oriented research; prevent; programs; protein intake; research study; response; skills; urinary

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.

项目概要 Tamara Isakova，医学博士，理学硕士正在申请以患者为导向的 K24 职业中期研究员奖 研究（POR）。她是西北大学肾脏科的医学副教授 大学范伯格医学院。她领导转化代谢与健康中心 公共卫生和医学研究所以及奥布莱恩肾脏核心的临床和转化核心 研究中心。伊萨科娃博士的研究重点是为新方法提供证据 改善慢性肾脏病（CKD）患者的心血管疾病结局。她拥有以下专业知识 流行病学研究、POR 和多中心临床试验，她还担任过以下项目的科学导师： 医学生、住院医生、研究员和初级教师。 K24 的支持将为 Isakova 博士提供 受保护的时间 1) 投入更多的时间来指导 POR 中不同的年轻研究者群体； 2）到 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 通过跨学科合作开辟新的科学领域； 4）补充对她的研究计划的支持 通过新的国立卫生研究院资助； 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 CKD 心血管疾病发病机制的机制贡献者。目前的提案构建 在此科学前提下，并扩展了 PI R01 支持的工作。项目 1 利用正在进行的工作 在 CKD Optimal Management with BInders 和 NicotinamidE (COMBINE) 试验中，这是一项多中心、 随机、双盲、安慰剂对照试验，测试了烟酰胺（阻断活性物质）的假设 肠道中的磷酸盐运输）和碳酸镧（磷酸盐结合剂）可以安全地降低血清 12 个月内 205 名患者的磷酸盐和成纤维细胞生长因子 (FGF23) 水平与安慰剂相比 CKD 阶段 3b-4。在 K24 的支持下，PI 将确定镧的功效是否 碳酸盐在某些亚组中更为明显，确定磷酸盐和 FGF23 的关系 降低心肌应变，并研究干预措施对下游产物的影响 烟酰胺和其他代谢物以及 T50（一种钙化生物标志物）。项目 2 利用了正在进行的工作 慢性肾功能不全队列 (CRIC) 研究是一项对约 4,000 名患有慢性肾功能不全的患者进行的观察性研究 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（一种次要的）可能可改变的决定因素 胆汁酸参与 CKD 血管钙化的发病机制。拟议目标的实施将 推进心血管疾病非传统危险因素领域的发展，提出潜在的治疗方法 PI 将在未来的介入研究中测试这些方法，并将为 POR 培训提供肥沃的土壤。