Mechanisms of Altered Neutrophil Trafficking in the Persistent Inflammation, Immunosuppression and Catabolism Syndrome

项目摘要 拟议的职业发展奖将为Vanessa Nomellini医学博士提供必要的支持 成为一名独立的科学调查员。诺梅里尼博士的研究目标是识别和克服 损伤和感染后免疫功能障碍的未知机制。特别是，诺梅里尼博士的 目标是更好地了解进展到慢性危重疾病状态的患者。与 她从目前的研究中获得了知识，她希望开发出早期应用的临床试验 干预措施，改善这些患者的预后。 目前的建议旨在研究中性粒细胞功能障碍的机制。 脓毒症后免疫抑制阶段，通常称为持续性炎症， 免疫抑制和分解代谢综合征(PICS)。这种状态与系统性疾病的持续迹象有关。 炎症，但由于T细胞耗尽和免疫细胞功能障碍而增加了感染的易感性。 虽然许多免疫细胞在这种状态下功能失调，但这项拟议的工作重点是机制 中性粒细胞功能障碍是理解PICS背后的病理生理学的门户 它们在根除病原体方面发挥了作用。本申请中的实验设计利用了小鼠模型 PICS，这是在诺梅里尼博士的实验室建立的，目的是阐明异常中性粒细胞的机制 使用体内和体外技术进行PICS期间的迁移。 这份提案中概述的职业发展计划包括一个由查尔斯博士领导的导师团队。 考德威尔和蒂莫西·普里茨博士以及包括迈克尔博士在内的奖学金监督委员会 爱德华兹担任外科主任，亚历克斯·兰奇博士担任 手术。虽然诺梅里尼博士在基础科学研究方面有广泛的背景，但她产生 进一步将在小鼠模型中观察到的结果转化为临床的强有力的临床试验大大低于- 发展起来的。本申请中建议的额外培训和指导是专门为 加强和提高她在临床试验设计方面的知识，以确保她的最终职业目标是 成功。为此，建议减轻她的临床和教育责任，为她提供 有75%的保护研究时间。她有机会获得优秀的研究设施和设备来完成 所有提议的研究。随着这些变化，以及她的部门主席和 科长，她将有足够的时间和支持，成功完成拟议的研究，如下 完成她的职业发展计划，并有效地调整自己，开始她的独立职业生涯 科学家。

Project Summary The proposed Career Development Award will provide Vanessa Nomellini, MD, PhD the support necessary to become an independent scientific investigator. Dr. Nomellini’s research goals are to identify and overcome the undiscovered mechanisms of immune dysfunction after injury and infection. In particular, Dr. Nomellini’s goals are to better understand the patients who progress to a state of chronic critical illness. With the knowledge she gains from the current studies, she hopes to develop clinical trials that will apply early interventions and improve outcomes for these patients. The current proposal aims to investigate the mechanisms of neutrophil dysfunction that occurs during the immunosuppressed phase after sepsis, commonly referred to as the Persistent Inflammation, Immunosuppression and Catabolism Syndrome (PICS). This state is associated with ongoing signs of systemic inflammation, but with increased susceptibility to infection due to T cell depletion and immune cell dysfunction. While a number of immune cells are dysfunctional in this state, this proposed work focuses on the mechanisms of neutrophil dysfunction as the gateway to understanding the pathophysiology behind PICS given the critical role they play in pathogen eradication. The experimental design in this application utilizes a murine model of PICS, which was established in Dr. Nomellini’s lab, to elucidate the mechanisms of aberrant neutrophil migration during PICS using in vivo and in vitro techniques. The career development plan outlined in this proposal includes a mentorship team led by Dr. Charles Caldwell and Dr. Timothy Pritts along with a scholarship oversight committee that includes Dr. Michael Edwards as the Chair of the Department of Surgery and Dr. Alex Lentsch as the Vice Chair of Research for Surgery. While Dr. Nomellini has an extensive background in basic science research, her ability to generate robust clinical trials to further translate the observations in mouse models into the clinic is significantly under- developed. The additional training and mentorship proposed in this application is specifically designed to strengthen and improve her knowledge on clinical trials design to ensure her ultimate career goals are successful. To this end, a reduction in her clinical and educational responsibilities is proposed to provide her with 75% protected research time. She has access to excellent research facilities and equipment to complete all proposed studies. With these changes, along with the complete support of her Department Chair and Section Chief, she will have adequate time and support to successfully complete the proposed studies, follow through with her career development plan and effectively align herself to launch her career as an independent scientist.