Kupffer Cell Survival and Function During the Evolution of Pseudomonas Sepsis

描述(由申请人提供)： 这项申请是为了支持Alix Share博士发展成为一名独立的研究员和一名有成就的临床医生兼科学家。加里·亨宁哈克博士将承担起导师的责任，确保职业发展计划的成功。阿沙雷博士目前正在攻读转化型生物医学博士学位。她已经完成了研究设计、统计学方法和研究生免疫学方面的教学培训。在此奖项期间，职业发展的具体领域将包括免疫学、微生物学和细胞生物学的进一步课程工作，以及与她的博士论文委员会的定期教育互动。本研究旨在探讨铜绿假单胞菌败血症时枯否细胞凋亡的机制及意义。肝脏是脓毒症的重要器官，因为它在细菌清除和细胞因子产生方面发挥作用。在目标1中，沙雷博士将在小鼠模型中研究假单胞菌败血症对肝脏细菌清除和库普弗细胞存活的影响。除原发感染外，败血症期间还会发生继发感染。在目标2中，沙雷博士将评估细菌易位引起的二次感染在脓毒症诱导的库普弗细胞凋亡中的作用。特别是，ashare博士将研究在肝脏细菌清除受损的情况下，细菌易位与多器官功能障碍综合征(MODS)的发展之间的关系。目的3研究脓毒症时枯否细胞凋亡的机制。具体地说，沙雷博士将研究肿瘤坏死因子α和凋亡信号调节激酶1在诱导库普弗细胞凋亡中的作用。在阿沙雷博士的整个职业发展过程中，她将与免疫学、微生物学、肝病学、生物统计学和研究设计以及肺部和重症监护医学方面的专家打交道。这种知识丰富的环境将有助于促进她的职业发展，在整个奖项期间提供充足的机会进行批判性审查。导师和学院都高度致力于沙雷博士的科学发展和学术成功。阿沙雷博士提出的研究计划具有重要的临床意义。脓毒症和MODS与高死亡率和沉重的成本负担有关。这项研究计划可以为脓毒症中MODS的病理生理学提供洞察力，并为未来的治疗试验提供方向。

DESCRIPTION (provided by applicant): This application is to support the development of Dr. Alix Ashare into an independent researcher and an accomplished clinician-scientist. Dr. Gary Hunninghake will assume the responsibility as mentor to ensure the success of the Career Development Plan. Dr. Ashare is currently enrolled in courses toward a Ph.D. in Translational Biomedicine. She has completed didactic training in study design, statistical methods, and graduate immunology. Specific areas of career development during this award will include further course work in immunology, microbiology, and cell biology, as well as regular educational interactions with her Ph.D. Thesis Committee. The proposed research investigates the mechanism and significance of Kupffer cell apoptosis during Pseudomonas sepsis. The liver is an important organ in sepsis because it plays a role in bacterial clearance and cytokine production. In Aim 1, Dr. Ashare will investigate the effect of Pseudomonas sepsis on hepatic bacterial clearance and Kupffer cell survival in a murine model. In addition to the primary infection, secondary infections occur during the course of sepsis. In Aim 2, Dr. Ashare will evaluate the role of secondary infection due to bacterial translocation of enteric organisms in the setting of sepsis-induced Kupffer cell apoptosis. In particular, Dr. Ashare will investigate the relationship between bacterial translocation and the development of multiple organ dysfunction syndrome (MODS) in the setting of impaired hepatic bacterial clearance. Aim 3 will be directed at investigating the mechanism of Kupffer cell apoptosis during Pseudomonas sepsis. Specifically, Dr. Ashare will investigate the role of tumor necrosis factor alpha and apoptosis signal-regulating kinase 1 in the induction of Kupffer cell apoptosis. Throughout Dr. Ashare's career development, she will interface with experts in immunology, microbiology, hepatology, biostatistics and study design, and pulmonary and critical care medicine. This intellectually rich environment will help foster her career development, providing ample opportunity for critical review throughout the period of this award. Both the mentor and the institution are highly committed to Dr. Ashare's scientific development and academic success. Dr. Ashare's proposed Research Plan has great clinical significance. Sepsis and MODS are associated with high mortality and a heavy cost burden. This Research Plan could provide insight into the pathophysiology of MODS in sepsis and provide direction for future therapeutic trials.