PPAR gamma in pediatric sepsis and the inflammatory response in obesity

描述(由申请人提供)：本提案是一个为期四年的课程和研究计划，旨在为我提供过渡到独立调查人员的手段。我是辛辛那提儿童医院医学中心重症监护医学部的儿科学助理教授，接受过分子流行病学和败血症相关基础科学研究方面的培训。本申请提供流行病学和免疫学的拟议课程，并对拟议的研究项目进行描述。脓毒症是一种临床实体，涉及大规模的全身炎症反应，可导致多器官功能障碍和死亡。全身生理变化会导致内皮损伤、细胞损伤和器官衰竭。核受体PPARg参与了脓毒症实验模型炎症反应的调节，但对儿童炎症反应的影响知之甚少。我们的初步数据表明，在实验动物模型和重症脓毒症儿童中，PPARg发生了改变。此外，在动物模型中，饮食也是脓毒症易感性的一个重要因素。该应用的中心假设是，PPARg途径在脓毒症患者中发生改变，饮食以PPARg依赖的方式进一步影响对脓毒症的炎症反应。这一假设将通过追求三个具体目标来验证：1)确定脓毒症儿童单核细胞中PPARg途径的变化；2)确定PPARg配体在败血症休克儿童单核细胞体外炎症反应中的治疗效果；3)确定PPARg在肥胖儿童对脓毒症易感性增加中的作用。在目标1下，我们将利用一种临床方法来研究败血症儿童外周血单核细胞中PPARg的变化。目的2采用体外单核细胞翻译的方法，研究PPARg配体在改变脓毒症炎症反应中的疗效。AIM 3将使用基础科学方法，在体内和体外研究将被用来确定PPARg在肥胖症败血症易感性增加中的作用。这项拟议的研究具有重要意义，因为它可以为脓毒症患者带来新的治疗方法，包括FDA批准的PPARg配体-噻唑烷二酮的潜在使用，它可以增强PPARg途径。 公共卫生相关性：这项调查的结果将为开发新的治疗方法提供有用的信息，以针对败血症儿童中发生的失衡。此外，它还将提供对与肥胖相关的炎症状态增加的了解，以及肥胖患者在危重疾病期间对更糟糕结果的易感性增加的理解。

DESCRIPTION (provided by applicant): This proposal represents a four-year curriculum and research plan that is designed to provide me with the means to transition to an independent investigator. I am an Assistant Professor in Pediatrics in the Division of Critical Care Medicine at Cincinnati Children's Hospital Medical Center with training in molecular epidemiology and sepsis-related basic science research. This application provides a proposed curriculum in epidemiology and immunology and a description of the proposed research project. Sepsis is a clinical entity that involves a massive systemic inflammatory response and can lead to multiple organ dysfunction and death. Systemic physiologic changes lead to endothelial injury, cellular damage and organ failure. The nuclear receptor, peroxisome proliferator-activated receptor-g (PPARg), is involved in the regulation of the inflammatory response in experimental models of sepsis but little is known about the effects in children. Our preliminary data suggest that PPARg is altered in experimental animal models and in critically ill children with sepsis. Furthermore we have demonstrated that diet is also an important factor of sepsis susceptibility in animal models. The central hypothesis of the application is that the PPARg pathway is altered in patients with sepsis and that diet further affects the inflammatory response to sepsis in a PPARg-dependent manner. This hypothesis will be tested by pursuing three specific aims: 1) Determine the alterations in the PPARg pathway in monocytes from children with sepsis; 2) Determine the therapeutic efficacy of PPARg ligands in the inflammatory response in ex vivo monocytes from children with septic shock; 3) Determine the role of PPARg in the increased susceptibility to sepsis in obesity. Under aim 1 we will utilize a clinical approach to investigate alterations in PPARg in peripheral blood monocytes from children with sepsis. Aim 2 will use a translational approach using ex vivo monocytes to investigate the therapeutic efficacy of PPARg ligands in altering the inflammatory response in sepsis. Aim 3 will use a basic science approach where in vivo and in vitro studies will be used to determine the role of PPARg in the increased susceptibility to sepsis in obesity. The proposed research is significant because it can lead to novel therapies for patients with sepsis, including the potential use of FDA-approved PPARg ligands, thiazolidinediones, which can augment the PPARg pathway. PUBLIC HEALTH RELEVANCE: The results of this investigation will provide useful information in developing new therapies to target the imbalance which occurs in children with sepsis. Furthermore, it will provide an understanding of the increased inflammatory state associated with obesity and of the increased susceptibility of obese patients to worse outcomes during critical illness.