Innate Immune Dysfunction Following Burn Inhalation Injury in Humans.

描述（由申请人提供）：候选人是一名烧伤重症外科医生，具有儿科和成人烧伤护理的临床专业知识。他之前有基础科学研究的背景，并致力于将这些技能应用于烧伤患者的免疫功能障碍研究。本K08申请的目的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，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志物发现的实验室。具体来说，候选人的短期职业目标是：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研究吸入急性毒素先天免疫激活作用的转化研究项目有关；2. 通过正式的课程学习，与研究人员建立合作关系，以及经验丰富的研究人员（正式和非正式）的指导，提高他在观察性和介入性临床研究的分析和设计能力；3. 继续收集数据，进一步完善未来的假设驱动提案，深入研究，目标是开发潜在的治疗策略，以减轻这些影响，以及演讲和出版物，使他能够在2017年申请R01。该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Aim 1中，患者肺部的先天免疫细胞在吸入性损伤和/或皮肤烧伤后发生早期（M2）和晚期（M1）的差异极化，这可以通过治疗逆转。在Aim 2特异性先天信号谱中，随着时间的推移，DAMPs浓度和特异性细胞因子谱的增加将预测吸入性损伤和/或皮肤烧伤后不良的临床结果。这些目标通过提供肺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候选人的职业发展。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的高级课程；2)指导和咨询团队，包括国际公认的独立资助的研究人员，他们在宿主-微生物相互作用，肺生物学和免疫学方面具有专业知识；3)旨在促进独立和国家认可的学术活动。最后，候选人的研究环境是基于一个杰出的学术研究机构（北卡罗来纳大学教堂山分校），可以使用美国国立卫生研究院资助的中心（包括环境医学哮喘和肺部生物学中心），这些中心是为支持拟议的研究而量身定制的。这种环境将提供一个富有成效和协作的氛围，以完成所描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.