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

基本信息

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
项目类别：
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

项目摘要

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）：该K23职业发展奖的支持将为Mikacenic博士提供有机会实现她成为人类免疫学和重症疾病十字路口的独立资助的转化调查员的长期目标。该提出的项目着重于米卡辛博士先前在细胞和分子实验室技术方面的经验的T调节细胞反应中的异质性。重要的是，它提供了Mikacenic博士所需的基本培训，以追求与患者急性呼吸遇险综合征（ARDS）直接相关的结果研究的目标。这将在短期内通过专家指导，教学课程以及旨在以实用方式实施知识的项目来完成。在研究环境方面，华盛顿大学将丰富的学术环境作为该国最高资金资助的研究机构之一。肺和重症监护医学的划分已经产生了许多成功的独立研究人员，尤其是在重症疾病领域。 Mikacenic博士通过与具有国际认可的非营利生物医学研究机构Benaroya Research Institute的T型细胞专家合作来扩大了这种环境。最重要的是，她与一个强大的指导团队包围着，具有重症疾病，免疫学，遗传学和流行病学方面的专业知识，以实现自己的目标。这项赠款中的研究重点是延长ARDS的机械通气。该综合征具有很高的死亡率，并可能导致幸存者的严重残疾，尤其是那些将长期重症监护病房留在该患者的研究计划中，Mikacenic博士的目的是定义人类T调节细胞的作用，即一种免疫抑制性淋巴细胞，在ARDS中延长的机械气流。人们认为这种细胞类型可以改善小鼠模型中肺损伤的分辨率，但缺乏人类的研究。她将确定T调节细胞的数量或功能是否与延长的机械通气有关。此外，Mikacenic博士将利用人Toll样受体1（TLR1）中的常见和功能遗传变异，作为一种可能改变这些细胞功能的机制。这些研究的发现将具有直接的患者影响。在综合征几乎没有治疗方案以改善患者预后的综合症中，改善的T调节细胞反应可能会提供一种新颖的治疗策略，以抑制过度炎症的炎症。这些研究的遗传性质还可以进一步个性化ARDS患者亚群的治疗策略。