Influence of TLR1 Polymorphisms on T-Regulatory Cells in ARDS

描述(由申请者提供)：K23职业发展奖的支持将为Mikacens博士提供机会，以实现她的长期目标，即成为一名在人类免疫学和危重疾病的十字路口独立资助的翻译研究人员。这项拟议的项目主要关注T调节细胞反应的异质性，借鉴了Mikacenen博士以前在细胞和分子实验室技术方面的经验。重要的是，它为Mikacens博士追求与患者急性呼吸窘迫综合征(ARDS)直接相关的结果研究的目标提供了所需的基础培训。这将在短期内通过专家指导、教学课程和一个旨在以实际方式实施她的知识的项目来实现。在研究环境方面，华盛顿大学作为美国国立卫生研究院资助最高的研究机构之一，提供了丰富的学术环境。肺和危重病医学司培养了许多成功的独立资助的研究人员，特别是在危重病领域。米卡西恩博士通过与贝纳罗亚研究所(Benaroya Research Institute)的T调节细胞专家合作，放大了这种环境。贝纳罗亚研究所是一家国际知名的非营利性生物医学研究机构。最重要的是，她身边有一支强大的导师团队，他们拥有危重疾病、免疫学、遗传学和流行病学方面的专业知识，以实现她的目标。这项赠款的研究重点是ARDS患者的长时间机械通气。这种综合征具有很高的死亡率，并可能导致幸存者的严重残疾，特别是那些将在这项以患者为导向的研究计划中长期住在重症监护病房的人。Mikacens博士的目标是确定人类T调节细胞在ARDS延长机械通气中的作用。这种细胞类型被认为可以提高小鼠模型中肺损伤的分辨率，但人类研究缺乏。她将确定T调节细胞的数量或功能是否与长时间的机械通气有关。此外，米卡西恩博士将利用人类Toll样受体1(TLR1)常见的功能性遗传变异作为改变这些细胞功能的一种机制。这些研究的结果将对患者产生直接影响。在一个几乎没有治疗选择来改善患者预后的综合征中，改进的T调节细胞反应可能提供一种新的治疗策略来抑制过度活跃的炎症。这些研究的遗传学性质也可能进一步使ARDS患者亚群的治疗策略个人化。

DESCRIPTION (provided by applicant): Support from this K23 Career Development Award will provide Dr. Mikacenic with the opportunity to meet her long-term goal of becoming an independently funded translational investigator at the crossroads of human immunology and critical illness. This proposed project focuses on heterogeneity in T-regulatory cell responses drawing on Dr. Mikacenic's previous experience in cellular and molecular laboratory based techniques. Importantly, it provides the fundamental training needed for Dr. Mikacenic to pursue her goal of outcomes research directly relevant to acute respiratory distress syndrome (ARDS) in patients. This will be accomplished in the short term by expert mentorship, didactic coursework, and a project designed to implement her knowledge in a practical manner. In terms of the research environment, the University of Washington provides a rich academic environment as one of the most highly NIH-funded research institutions in the country. The Division of Pulmonary and Critical Care Medicine has produced many successful independently funded researchers particularly in the area of critical illness. Dr. Mikacenic has amplified this environment by collaborating with the T-regulatory cell experts at the Benaroya Research Institute, a non-profit biomedical research facility with international recognition. Most importanty, she has surrounded herself with a strong mentorship team with expertise in critical illness, immunology, genetics and epidemiology to obtain her goals. The research in this grant focuses on prolonged mechanical ventilation in ARDS. This syndrome carries high mortality and can lead to significant disability in survivors, particularly those will long intensive care unit stays In this patient oriented research plan, Dr. Mikacenic aims to define the role of human T-regulatory cells, an immunosuppressive lymphocyte, in prolonged mechanical ventilation in ARDS. This cell type is thought to improve resolution of lung injury in mouse models but human research is lacking. She will determine if T-regulatory cell quantity or function is associated with prolonged mechanical ventilation. Additionally, Dr. Mikacenic will take advantage of common and functional genetic variation in human Toll-like receptor 1 (TLR1) as a mechanism by which the function of these cells may be altered. The findings of these studies will have direct patient impact. In a syndrome with few treatment options to improve patient outcomes, improved T- regulatory cell responses may provide a novel treatment strategy to dampen over-exuberant inflammation. The genetic nature of these studies may also further personalize treatment strategies for subpopulations of ARDS patients.