Pathological Interaction of Obesity and Sepsis: Role of Adipokines

描述（由申请人提供）：这个职业发展奖提出了一个为期四年的培训计划，为董事会认证的重症监护医生科学家。Vidula Vachharajani博士，医学博士。Vachharajani博士开发并使用了几种肥胖小鼠模型来研究败血症期间发生的内皮功能障碍。已知肥胖会加剧许多免疫和炎症反应，但增强反应的精确分子和细胞机制尚不清楚。肥胖小鼠模型的初步数据表明，败血症中过度的炎症与肥胖相关的炎症表型有关。本研究计划的目的是检验脂联素减少和P-选择素表达增加介导肥胖动物和脓毒症患者内皮功能障碍增强的假设。本研究的具体目的是：（1）利用基因修饰技术，研究脂联素对瘦小鼠和肥胖小鼠脑微循环中白细胞和血小板粘附、P-选择素表达、血脑屏障功能以及生存率的影响。盲肠结扎穿刺法可诱发脓毒症。IA将评估脂联素缺陷（Ad ko）瘦小鼠和ob/ob小鼠中的炎症反应。图1B将评估具有手术诱导的脓毒症的Ad过表达（Ad tg）瘦小鼠和ob/ob小鼠中的炎症反应。(2)我们将用小鼠脂联素（Adiponectin，Ad）预处理手术诱导脓毒症的瘦ob/ob和饮食诱导肥胖（diet induced obese，DIO）小鼠，以评估炎症反应对白细胞和血小板粘附、P-选择素表达、脑微循环中血脑屏障功能和动物存活的影响。教育计划的目标是进一步完善和发展研究技能，补充Vachharajani博士以前的研究经验。她的主要导师，查尔斯麦考尔，医学博士，是WFU转化科学研究所所长和内科学教授。他是一位有着超过35年研究经验的知名医生科学家，并指导了40多名学员。芭芭拉Yoza，博士，是研究助理教授在系。他与McCall博士密切合作，作为共同PI指导他的研究实验室。Kevin High博士，医学博士，理学硕士，是内科学教授，将指导Vachharajani博士的教育（分子医学博士课程的有限课程）和专业（在校内和校外水平的晋升）发展。相关性（见说明）：病态肥胖脓毒症患者的发病率和资源利用率增加，进一步增加了他们的护理成本。这项工作的发现可能允许设计新的治疗方法来改善肥胖人群脓毒症的结局。随着越来越多的肥胖-脓毒症患者的发病率增加，这一建议具有很大的潜在重大公共卫生影响。

DESCRIPTION (provided by applicant): This career development award proposes a four-year training program for a board certified Critical Care physician scientist. Dr. Vidula Vachharajani, MD. Dr. Vachharajani has developed and uses several murine models of obesity to study endothelial dysfunction that occurs during sepsis. Obesity is known to exacerbate many immune and inflammatory responses, but the precise molecular and cellular mechanism(s) of the enhanced response is unknown. The preliminary data in obese mouse models suggest that the exaggerated inflammation in sepsis is related to an inflammatory phenotype associated with obesity. The objective of the research plan is to test the hypothesis that decreased adiponectin and increased P-selectin expression mediate the enhanced endothelial dysfunction seen in obese animals and humans with sepsis. The SPECIFIC AIMS to test the hypothesis are: (1) Using genetic modification, we will assess the effect of adiponectin on leukocyte and platelet adhesion, P-selectin expression, and blood-brain barrier function in cerebral microcirculation in lean and obese mice and on survival. Sepsis will be induced by cecal ligation puncture method. IA will assess the inflammatory response in adiponectin-deficient (Ad ko) lean and ob/ob mice. 1B will assess the inflammatory response in Ad over-expressing (Ad tg) lean and ob/ob mice with surgically induced sepsis. (2) We will use murine adiponectin (Ad) pre-treatment in lean ob/ob and diet induced obese (DIO) mice with surgically induced sepsis to assess the inflammatory response on leukocyte and platelet adhesion, P-selectin expression, blood-brain barrier function in the cerebral microcirculation and survival ofthe animals. The objective of the education plan is to further refine and develop research skills that complement Dr. Vachharajani's previous research experience. Her primary mentor, Charles McCall, MD, is Director ofthe WFU Translational Science Institute and Professor of Internal Medicine. He is an established physician scientist with over 35 years of research experience and has mentored over 40 trainees. Barbara Yoza, PhD, is Research Asst. Professor in the Dept. of Surgery and works closely with Dr. McCall as co-PI in directing his research laboratories. Dr. Kevin High, MD, MS, is Professor of Internal Medicine and will mentor Dr. Vachharajani's education (limited course of study in Molecular Medicine doctoral program) and professional (promotion both at the intramural and extramural level) development. RELEVANCE (See instructions): Increased morbidity and resource utilization in morbidly obese septic patients increases their cost of care further. Discoveries from this work may allow design of novel therapies to improve outcome of sepsis in obese humans. With rising number of obese-septic patients with increased morbidity, this proposal has great potential for substantial public health implications.