The Assessment of Acute Kidney Injury Sub-phenotypes in the Intensive Care Unit

项目概要/摘要 Pavan Bhatraju，医学博士，理学硕士计划在以下领域担任分子流行病学家医生科学家 重症监护室（ICU）中的急性肾损伤（阿基）。拟议职业发展的目标 该奖项是提供必要的培训，研究方法，以促进博士Bhatraju的过渡到独立的 research.华盛顿大学（UW）肺科和 重症监护医学（PCCM）和肾脏研究所是杰出的。他将继续他的工作 在华盛顿大学的Mark Wurfel博士（PCCM）和Jonathan Himmelfarb博士（肾脏病学）的指导下。 他的多学科研究团队的合作者跨越了基因组科学（Gail Jarvik博士）， 流行病学和生物统计学（Ronit Katz博士）以及转化研究在阿基研究中的应用 (Dr. Chirag Parik）。为了补充这个研究团队的支持，Bhatraju博士将增加他的硕士学位。 在流行病学科学与先进的课程在全国著名的公共卫生的华盛顿大学学校。 阿基在ICU中很常见，与发病率和死亡率相关。目前，我们没有有效的 阿基的药物治疗。药物开发的局限性可能部分由生物学原因解释。 和阿基表型患者的临床异质性。为了解决这些局限性，我们的实验室 使用创新的建模方法鉴定了两种不同的阿基亚表型（也称为内型）， 潜在阶级分析我们发现两种阿基亚表型具有不同的临床特征， 生物标志物模式和短期不良结局的风险。我们还开发并验证了一个3变量 预测模型，以前瞻性地识别阿基亚表型。总的来说，这些发现提供了 Bhatraju博士的K23研究计划的基础。本研究的目的包括：1） 评价1年时阿基亚表型与主要不良肾脏事件的相关性; 2）确定 与阿基亚表型的发展相关的遗传风险因素，以及; 3）确定特定的 阿基亚型之间的病理生理学差异通过靶向尿蛋白分析。 该奖项将提供基因组科学，生物统计学，先进的流行病学， 还能拓宽他的实验室技能该提案利用了Bhatraju博士独特的多个访问权限 危重患者队列，获得UW的研究基础设施，以招募前瞻性ICU队列， 尿液，血浆和DNA样本，并获得世界一流的教学培训计划，在华盛顿大学学院 公共卫生他的总体研究目标是利用分子流行病学技术， 基于病理生理学的阿基患者分类，以改善风险预测， 遗传风险因素，并为预防和治疗阿基的发展提供基于精确度的策略 重症监护室在K23的支持下，Bhatraju博士设计的研究和教育议程将帮助他 实现他的长期目标，成为一名独立的翻译研究者进行阿基研究。

Project Summary/Abstract Pavan Bhatraju, MD, MSc plans for a career as a molecular epidemiologist physician scientist in the field of acute kidney injury (AKI) in the intensive care unit (ICU). The objective of the proposed career development award is to provide necessary training in research methods to facilitate Dr. Bhatraju’s transition to independent research. The mentorship available at the University of Washington (UW) in the Division of Pulmonary and Critical Care Medicine (PCCM) and the Kidney Research Institute are outstanding. He will continue his work under the mentorship of Drs. Mark Wurfel (PCCM) and Jonathan Himmelfarb (Nephrology) at the UW. Collaborators on his multi-disciplinary research team span the disciplines of genome sciences (Dr. Gail Jarvik), epidemiology and biostatistics (Dr. Ronit Katz) and the application of translational research to the study of AKI (Dr. Chirag Parik). To complement the support from this research team, Dr. Bhatraju will augment his Masters in Science in Epidemiology with advanced coursework at the nationally-renowned UW School of Public Health. AKI is common in the ICU and is associated with morbidity and mortality. Currently we have no effective pharmacological therapy for AKI. Limitations in drug development may be partly explained by the biological and clinical heterogeneity in patients included in the AKI phenotype. To address these limitations, our lab has identified two distinct AKI sub-phenotypes (also known as endotypes) using an innovative modeling approach, latent class analysis. We found that the two AKI sub-phenotypes had different clinical characteristics, biomarker patterns and risk of poor short-term outcomes. We also developed and validated a 3-variable prediction model to prospectively identify the AKI sub-phenotypes. Overall, these findings provide the foundation for Dr. Bhatraju’s K23 research proposal. The objectives of the proposed research include: 1) evaluate the association of AKI sub-phenotypes with major adverse kidney events by 1 year; 2) determine the genetic risk factors associated with the development of AKI sub-phenotypes, and; 3) identify specific pathophysiologic differences between the AKI sub-phenotypes through a targeted urinary protein analysis. This award will provide essential research training in genome sciences, biostatistics, advanced epidemiology and will broaden his bench lab skillset. This proposal leverages Dr. Bhatraju’s unique access to multiple critically ill cohorts, access to a research infrastructure at the UW to enroll a prospective ICU cohort collecting urine, plasma and DNA samples and access to world-class didactic training program at the UW School of Public Health. His overall research goal is to use techniques of molecular epidemiology to develop a pathophysiologic based classification of patients with AKI to improve risk prognostication, discover novel genetic risk factors and inform precision based strategies to prevent and treat the development of AKI in the ICU. With the support of this K23, the research and education agenda Dr. Bhatraju has devised will assist him in achieving his long-term goal of becoming an independent translational investigator conducting AKI research.