Kupffer Cell Survival and Function During the Evolution of Pseudomonas Sepsis

描述（由申请人提供）： 本申请旨在支持阿利克斯阿沙尔博士发展成为一名独立研究人员和一名有成就的临床科学家。加里亨宁哈克博士将承担导师的责任，以确保职业发展计划的成功。Ashare博士目前正在攻读博士学位。转化生物医学她已经完成了研究设计、统计方法和研究生免疫学方面的教学培训。在此期间，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，以及与她的博士定期教育互动。论文委员会。本研究旨在探讨假单胞菌脓毒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中起作用。在目标1中，Ashare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枯否细胞存活的影响。除了原发性感染外，继发性感染在脓毒症过程中发生。在目标2中，Ashare博士将评价由于肠道微生物细菌移位引起的继发性感染在脓毒症诱导的枯否细胞凋亡中的作用。特别是，Ashare博士将研究在肝脏细菌清除受损的情况下，细菌移位与多器官功能障碍综合征（MODS）发展之间的关系。目的3探讨假单胞菌脓毒症时枯否细胞凋亡的机制。具体来说，Ashare博士将研究肿瘤坏死因子α和凋亡信号调节激酶1在诱导枯否细胞凋亡中的作用。在Ashare博士的职业发展过程中，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进行交流。这种智力丰富的环境将有助于促进她的职业发展，在整个颁奖期间提供充分的批判性审查机会。导师和机构都高度致力于Ashare博士的科学发展和学术成功。Ashare博士提出的研究计划具有重要的临床意义。败血症和MODS与高死亡率和沉重的费用负担相关。本研究计划可为脓毒症患者MODS的病理生理学提供深入的见解，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.