Influence of TLR1 Polymorphisms on T-Regulatory Cells in ARDS

TLR1 多态性对 ARDS 调节性 T 细胞的影响

• 批准号: 8616243
• 负责人: Carmen R Mikacenic
• 金额: $ 15.68万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-06 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616243
• 关键词: Address; Adult Respiratory Distress Syndrome; Affect; Agonist; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Area; Biomedical Research; Blood capillaries; Bronchoalveolar Lavage Fluid; Candidate Disease Gene; Cell Surface Proteins; Cell physiology; Cells; Cessation of life; Clinical Research; Complication; Country; Critical Care; Critical Illness; Data; Development; Environment; Epigenetic Process; Epithelial; Family; Flow Cytometry; Fright; Functional disorder; Funding; Generations; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Grant; Heterogeneity; Human; Hyaluronan; Immune response; Immune system; Immunology; Immunosuppressive Agents; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Institution; Intensive Care Units; International; Intervention; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Liquid substance; Lung; Lymphocyte; Measures; Mechanical ventilation; Medicine; Mentorship; Molecular; Molecular Weight; Mus; Nature; Organ; Outcome; Outcomes Research; Pathway interactions; Patients; Pattern; Phenotype; Play; Pneumonia; Prospective Studies; Recovery; Regulatory T-Lymphocyte; Research; Research Institute; Research Personnel; Resolution; Risk; Role; Sepsis; Severities; Signal Transduction; Survivors; Syndrome; Techniques; Testing; Toll-Like Receptor 1; Toll-like receptors; Training; Trauma; United States National Institutes of Health; Universities; Variant; Ventilation Test; Washington; Work; base; capillary; cell type; cost; design; disability; experience; genetic epidemiology; improved; lung injury; meetings; mortality; mouse model; novel; pathogen; patient oriented research; peripheral blood; prevent; promoter; public health relevance; research facility; response; risk variant; skills; treatment strategy

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.

描述（由申请人提供）：来自K23职业发展奖的支持将为Mikacenic博士提供机会，以实现她成为人类免疫学和危重病十字路口独立资助的翻译研究者的长期目标。这个项目的重点是利用Mikacenic博士以前在细胞和分子实验室技术方面的经验，研究T调节细胞反应的异质性。重要的是，它为Mikacenic博士提供了所需的基本培训，以实现她与患者急性呼吸窘迫综合征（ARDS）直接相关的结果研究目标。这将在短期内通过专家指导，教学课程和旨在以实际方式实施她的知识的项目来完成。在研究环境方面，华盛顿大学提供了丰富的学术环境，作为美国NIH资助最多的研究机构之一。肺和重症监护医学部已经产生了许多成功的独立资助的研究人员，特别是在危重病领域。Mikacenic博士通过与Benaroya研究所的T调节细胞专家合作，扩大了这种环境，Benaroya研究所是一家国际公认的非营利性生物医学研究机构。最重要的是，为了实现她的目标，她身边有一个强大的导师团队，他们在重症、免疫学、遗传学和流行病学方面都有专业知识。这项研究的重点是ARDS的长期机械通气。这种综合征的死亡率很高，并可能导致幸存者的严重残疾，特别是那些将长期留在重症监护病房的人。在这项以患者为导向的研究计划中，Mikacenic博士旨在确定人类T调节细胞（一种免疫抑制淋巴细胞）在ARDS长期机械通气中的作用。这种细胞类型被认为可以提高小鼠模型肺损伤的分辨率，但缺乏人体研究。她将确定T调节细胞的数量或功能是否与长期机械通气有关。此外，Mikacenic博士将利用人类Toll样受体1（TLR1）中的常见和功能性遗传变异作为这些细胞功能可能改变的机制。这些研究的结果将对患者产生直接影响。在几乎没有治疗选择来改善患者结果的综合征中，改善的T调节细胞应答可以提供一种新的治疗策略来抑制过度旺盛的炎症。这些研究的遗传性质也可能进一步个性化治疗策略的ARDS患者亚群。