Acute Adipose Inflammation as a Contributor to Acute Kidney Injury After Trauma

描述（由申请人提供）：拟议项目的广泛目标是：1）检验脂肪组织增强的全身炎症反应是肥胖与严重创伤后急性肾损伤（阿基）相关性的基础的假设，2）确定脂肪分布（内脏与皮下）是否影响这种相关性，3）训练 在以患者为导向的转化阿基研究中的申请人，以及4）为申请人提供个性化的指导，以确保他过渡到独立研究者的角色。阿基在危重病中很常见。阿基使ICU护理更加复杂，与死亡率大幅增加相关，并增加了幸存者终末期肾病的风险。在美国，每年有超过200万人因受伤住院，超过三分之一的危重患者 受伤的创伤患者发展阿基。然而，阿基的病理生理学仍不完全清楚。我们发表了一项研究，显示体重指数（BMI）与严重创伤后阿基有很强的相关性。我们额外的初步研究表明，多余的脂肪组织，而不是瘦体重，解释了这种关联。对炎症在阿基发病机制中的关键作用的不断理解，加上我们机构最近的研究表明脂肪组织是响应急性刺激的炎症介质的重要来源，指出脂肪增强全身炎症反应对创伤的作用是肥胖-AKI关系的潜在机制。该提案概述了在现有的危重创伤患者队列中研究这种机制的计划。利用该人群特有的计算机断层扫描（CT）的近乎一致的临床使用，将确定精确的基于CT的肥胖测量与阿基的关联，以确认肥胖-AKI关联。将在这些受试者中测试入院血浆炎症介质水平与肥胖和随后的阿基两者的关联。将在创伤患者和健康对照的脂肪组织中比较这些介质的表达，以测试脂肪对创伤的全身炎症反应和相关阿基风险的贡献。申请人将参加由高级流行病学家、生物统计学家、放射学家和实验室专家指导的严格的教学课程培训计划。他将获得cohrt研究指导，分子实验室技术，新的肥胖措施，先进的统计方法和肾脏流行病学的技能。导师及顾问委员会会定期检讨申请人在研究、出版及事业发展方面的基准。促进拟议的目标是一个环境，提供临床研究的专业知识，在一个合作的设置，数据库和统计支持，以及核心研究实验室的血浆和组织研究。通过开展拟议的研究和培训计划，申请人将为理解阿基病理生理学做出重大贡献，成为成熟的研究者，并准备成功竞争未来项目的R 01资金，旨在寻找针对阿基高风险人群的新型治疗靶点。

DESCRIPTION (provided by applicant): The broad objectives of the proposed project are to: 1) test the hypothesis that a systemic inflammatory response potentiated by adipose tissue underlies the association of obesity with acute kidney injury (AKI) after major trauma, 2) determine if adipose distribution (visceral versus subcutaneous) affects this association, 3) train the applicant in patient-oriented translational AKI research, and 4) provide the applicant with individualized mentoring to ensure his transition to the role of an independent investigator. AKI is common in critical illness. AKI makes ICU care more complex, is associated with a substantial mortality increase, and increases the risk of end stage renal disease in survivors. Over 2 million people are hospitalized for injury each year in the United States, and over one-third of critically ill trauma patients develop AKI. AKI pathophysiology, however, remains incompletely understood. We published a study showing a strong association of body mass index (BMI) with AKI after major trauma. Our additional preliminary studies suggest that excess adipose tissue, not lean mass, explains this association. The evolving understanding of the key role of inflammation in AKI pathogenesis, coupled with recent studies from our institution suggesting adipose tissue is a significant source of inflammatory mediators in response to acute stimuli, point toward adipose potentiation of the systemic inflammatory response to trauma as a potential mechanism underlying the obesity-AKI relationship. This proposal outlines a plan to study this mechanism in an existing cohort of critically ill trauma patients. Leveraging the near-uniform clinical use of computed tomography (CT) unique to this population, the association with AKI of precise CT-based adiposity measures will be determined to confirm the adiposity-AKI association. The association of admission plasma inflammatory mediator levels with both obesity and subsequent AKI will be tested in these subjects. Expression of these mediators will be compared in adipose tissue of trauma patients and healthy controls to test the contribution of adipose to the systemic inflammatory response to trauma and the associated AKI risk. The applicant will engage in a rigorous training program of didactic course work and mentoring by senior epidemiologists, biostatisticians, radiologists, and lab experts. He will gain skills in cohrt study conduct, molecular laboratory techniques, novel obesity measures, advanced statistical methodologies, and renal epidemiology. The applicant's attainment of benchmarks in research, publication, and career development will be regularly reviewed by his mentors and advisory committee. Facilitating the proposed aims is an environment which provides clinical research expertise in a collaborative setting, database and statistical support, and core research labs for plasma and tissue study. Through the conduct of the proposed study and training plan, the applicant will make significant contributions to the understanding of AKI pathophysiology, mature as an investigator, and prepare to compete successfully for R01 funding of future projects aimed at finding novel therapeutic targets tailored to populations at high risk for AKI.