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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：
9271218
负责人：
Carmen R Mikacenic
金额：
$ 18.9万
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/9271218
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 Environment Epigenetic Process Epithelial FOXP3 gene Family Flow Cytometry Foundations Fright Functional disorder Funding Generations Genetic Genetic Polymorphism Genetic Variation Genotype Goals Grant Heterogeneity Human Hyaluronan Immune response Immune system Immunology Immunosuppressive Agents Impairment 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 Patient-Focused Outcomes Patients Pattern Phenotype Play Prospective Studies Pulmonary Inflammation Recovery Regulatory T-Lymphocyte Research Research Institute Research Personnel Resolution Risk Role Sepsis Severities Signal Transduction Survivors Syndrome TLR1 gene Techniques Testing Toll-like receptors Training Trauma United States National Institutes of Health Universities Variant Ventilation Test Washington Work base capillary cell type collaborative environment cost design disability experience genetic epidemiology improved lung injury mortality mouse model novel novel therapeutics pathogen patient oriented research peripheral blood personalized medicine prevent promoter public health relevance research facility response risk variant skill acquisition translational scientist 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）：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疾病十字路口独立资助的转化研究者的长期目标。该计划的重点是利用Mikacenic博士之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博士提供了必要的基础培训，以追求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，说教式课程和一个旨在以实际方式实现她的知识的项目来完成。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多的研究机构之一，提供了丰富的学术环境。肺和危重症医学部已经培养了许多成功的独立资助的研究人员，特别是在危重症领域。Mikacenic博士通过与Benaroya研究所（一家国际认可的非营利性生物医学研究机构）的t调节细胞专家合作，扩大了这种环境。最重要的是，她身边有一个强大的导师团队，他们在危重疾病、免疫学、遗传学和流行病学方面具有专业知识，以实现她的目标。本基金的研究重点是ARDS的延长机械通气。该综合征具有高死亡率，并可导致幸存者严重残疾，特别是那些长期住在重症监护病房的患者。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患者长时间机械通气中的作用。在小鼠模型中，这种细胞类型被认为可以改善肺损伤的分辨率，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延长机械通气有关。此外，Mikacenic博士将利用人类toll样受体1 （TLR1）的常见和功能性遗传变异作为改变这些细胞功能的机制。这些研究的结果将对患者产生直接影响。在很少有治疗选择来改善患者预后的综合征中，改善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。这些研究的遗传性质也可能进一步个性化ARDS患者亚群的治疗策略。