Innate Immune Dysfunction Following Burn Inhalation Injury in Humans.

描述(由申请人提供)：应聘者是一名烧伤重症监护外科医生，在儿童和成人烧伤护理方面具有临床专业知识。他之前在基础科学研究方面的背景，并承诺将这些技能应用于烧伤患者免疫功能障碍的研究。K08提案的目标是获得所需的高级机械培训，以实现候选人的长期职业目标，即成为一名独立资助的内科科学家，领导一个专注于开发吸入性损伤新疗法和新生物标记物发现的实验室。候选人在这项提议中的短期职业目标是：1.获得目前在他的专业领域之外的知识和技能，这些知识和技能与建立一个转换研究项目相关，该项目研究吸入急性毒素激活天然免疫的作用；2.通过正式的课程，与研究人员建立合作关系，以及有经验的研究人员的指导(正式和非正式)，提高他在分析和设计观察性和干预性临床研究方面的能力；3.继续收集数据，并进一步完善假说驱动的建议，用于未来的深入研究，目标是开发潜在的治疗策略来减轻这些影响，以及使他能够在2017年申请R01的演示和出版物。候选人的总体研究目标是了解吸入性损伤患者对细菌感染易感性增加的机制。候选人假设，在吸入性损伤和/或皮肤烧伤后，患者肺内的先天免疫细胞在早期(M2)和晚期(M1)经历了差异极化，这种差异极化可以通过治疗来逆转。在AIM 2中，吸入性损伤和/或皮肤烧伤后，特定的先天信号转导谱、随时间增加的DAMPS浓度和特定的细胞因子谱将预测不良的临床结果。这些目的是通过提供肺部生物学机械方面的培训以及先天免疫功能障碍的研究来支持应聘者的职业发展。候选人培训计划的其他关键要素包括：1)计算生物学和统计建模方面的高级课程；2)指导和咨询团队，其中包括国际公认的、独立资助的具有宿主-微生物相互作用、肺部生物学和免疫学专业知识的研究人员；以及3)旨在促进独立性和国家认知度的学术活动。最后，候选人的研究环境是在一个著名的学术研究机构(北卡罗来纳大学教堂山分校)，可以访问NIH资助的中心(包括环境医学哮喘和肺生物学中心)，这些中心是为支持拟议的研究而量身定做的。这种环境将提供一个富有成效和协作的氛围，在其中完成所述的研究和培训目标。

DESCRIPTION (provided by applicant): The candidate is a Burn Critical Care Surgeon with a clinical expertise in pediatric and adult Burn care. His previous background in basic sciences research and an established commitment to apply these skills to the study immune dysfunction in burn patients. The objective of this K08 proposal is to obtain the advanced mechanistic training required to achieve the candidate's long-term career goal of becoming an independently funded physician-scientist, leading a laboratory focused on developing novel therapeutics for inhalation injury and novel biomarker discovery. Specifically the candidate's short-term career goals of this proposal are: 1. Gain knowledge and skills that are currently outside his field of expertise that are relevant to establish a translational research project studying the role of innate immune activation by inhaled acute toxins; 2. Improve his abilities in the analysis and design of both observational and interventional clinical research through formal coursework, establishing collaborations with researchers, and mentoring (formal and informal) from experienced investigators; 3. Continue to collect data and further refine a hypothesis driven proposal for future, in depth studies with the goal of developing potential therapeutic strategies to mitigate these effects, along with presentations and publications that will allow him to apply for a R01 in 2017. The candidate's overall research goal is to understand the mechanism of increased susceptibility to bacterial infections in patients with inhalation injuries. The candidat hypothesizes, in Aim 1 the Innate immune cells in patients' lungs undergo differential polarization early (M2) and late (M1) after inhalation injury and / or cutaneous burn that can be reversed therapeutically. In Aim 2 specific innate signaling profiles, increased concentrations of DAMPs and specific cytokine profiles over time will be predictive of poor clinical outcome after inhalation injury and / or cutaneous burn. These aims support the candidate's career development by providing training in mechanistic aspects of lung biology, as well as the study of innate immune dysfunction. Additional key elements of the candidate's training plan include: 1) advanced coursework in computational biology and statistical modeling; 2) a mentorship and advising team, which includes internationally-recognized, independently-funded investigators with expertise in host-microbial interactions, lung biology, and immunology; and 3) scholarly activities designed to foster independence and national recognition. Finally, the candidate's research environment is based in a pre- eminent academic research institution (the University of North Carolina at Chapel Hill) with access to NIH- funded centers (including the Center for Environmental Medicine Asthma and Lung Biology) that are tailored to support the proposed studies. This environment will provide a productive and collaborative atmosphere in which to accomplish the described research and training goals.