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

急性脂肪炎症是创伤后急性肾损伤的一个原因

• 批准号: 8425800
• 负责人: Michael G. S. Shashaty
• 金额: $ 15.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8425800
• 关键词: Abdomen; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adipose tissue; Admission activity; Advisory Committees; Affect; Animal Model; Area; Benchmarking; Biological Markers; Body mass index; Caring; Chemosensitization; Chronic; Clinical; Clinical Investigator; Clinical Research; Cohort Studies; Complex; Coupled; Critical Illness; Data; Databases; Densitometry; Diabetes Mellitus; Distant; End stage renal failure; Endotoxemia; Ensure; Environment; Epidemiologist; Epidemiology; Fatty acid glycerol esters; Functional disorder; Funding; Future; Gene Expression Profiling; Generations; Hospitalization; Human; Hypertension; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Institution; Interleukin-6; Intervention; Investigation; Kidney; Knowledge; Laboratories; Leptin; Light; Link; Measures; Mediating; Mediator of activation protein; Mentors; Mentorship; Messenger RNA; Methodology; Modeling; Molecular; Monocyte Chemoattractant Protein-1; Motion; Obesity; Organ; Pathogenesis; Patients; Plasma; Population; Publications; Publishing; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Scanning; Sepsis; Serum; Severities; Slice; Source; Stimulus; Survivors; Techniques; Testing; Tissue Sample; Tissue-Specific Gene Expression; Tissues; Training; Training Programs; Trauma; Tumor Necrosis Factor-alpha; United States; Visceral; Work; X-Ray Computed Tomography; adipokines; base; career development; chemokine; cohort; cytokine; high risk; human disease; injury prevention; mortality; mouse model; new therapeutic target; novel; patient oriented; prevent; public health relevance; radiologist; resistin; response; response to injury; skills; stem; subcutaneous; tissue trauma

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.

描述(由申请人提供)：拟议项目的主要目标是：1)测试脂肪组织增强的全身炎症反应是严重创伤后肥胖与急性肾损伤(AKI)联系的基础的假设，2)确定脂肪分布(内脏与皮下)是否影响这种联系，3)培训 申请人在面向患者的转化性AKI研究中，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人员的角色。Aki在危重疾病中很常见。AKI使ICU护理更加复杂，与死亡率的大幅增加有关，并增加了幸存者患终末期肾脏疾病的风险。在美国，每年有200多万人因受伤而住院，其中超过三分之一的人伤势严重 疾病创伤患者会发展成AKI。然而，Aki的病理生理学仍不完全清楚。我们发表的一项研究表明，严重创伤后体重指数(BMI)与AKI之间存在很强的相关性。我们的其他初步研究表明，解释这种联系的是过量的脂肪组织，而不是瘦的质量。对炎症在AKI发病机制中的关键作用的认识不断发展，加上本研究所最近的研究表明，脂肪组织是急性刺激反应中炎症介质的重要来源，这表明脂肪增强了创伤后全身炎症反应，这是肥胖与AKI关系的潜在机制。这项提案概述了在现有的危重创伤患者队列中研究这一机制的计划。利用这一人群特有的计算机断层扫描(CT)几乎一致的临床应用，将确定基于CT的精确肥胖测量与AKI的相关性，以确认肥胖症与AKI的关联。入院时血浆炎症介质水平与肥胖和随后的AKI之间的关系将在这些受试者中进行测试。这些介质的表达将在创伤患者和健康对照组的脂肪组织中进行比较，以测试脂肪对创伤引起的全身炎症反应的贡献以及相关的AKI风险。申请者将参加由资深流行病学家、生物统计学家、放射科医生和实验室专家指导的教学课程工作和指导的严格培训计划。他将获得COHRT研究指导、分子实验室技术、新的肥胖测量方法、高级统计方法和肾脏流行病学方面的技能。申请人的导师和咨询委员会将定期审查申请人在研究、出版和职业发展方面达到基准的情况。促进拟议的AIMS的环境是一个在协作环境中提供临床研究专业知识的环境、数据库和统计支持，以及血浆和组织研究的核心研究实验室。通过实施拟议的研究和培训计划，申请者将对了解AKI的病理生理学做出重大贡献，成为一名成熟的研究人员，并准备成功竞争R01未来项目的资金，旨在寻找适合AKI高危人群的新治疗靶点。