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）：K23 职业发展奖的支持将为 Mikacenic 博士提供实现她的长期目标的机会，即成为人类免疫学和危重疾病十字路口的独立资助的转化研究者。该拟议项目利用 Mikacenic 博士之前在细胞和分子实验室技术方面的经验，重点研究 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础培训，以实现与患者急性呼吸窘迫综合征 (ARDS) 直接相关的结果研究目标。这将通过专家指导、教学课程和旨在以实际方式运用她的知识的项目在短期内完成。在研究环境方面，华盛顿大学作为美国NIH资助最多的研究机构之一，提供了丰富的学术环境。肺科和重症监护医学部培养了许多成功的独立资助的研究人员，特别是在危重疾病领域。 Mikacenic 博士通过与贝纳罗亚研究所（一家具有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，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。此项资助的研究重点是 ARDS 患者的长期机械通气。这种综合征死亡率很高，并可能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幸存者。在这项以患者为导向的研究计划中，Mikacenic 博士旨在明确人类 T 调节细胞（一种免疫抑制淋巴细胞）在长期生存中的作用。 ARDS 中的机械通气。这种细胞类型被认为可以提高小鼠模型肺损伤的解决率，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时间机械通气相关。此外，Mikacenic 博士将利用人类 Toll 样受体 1 (TLR1) 中常见的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。在改善患者预后的治疗选择很少的综合征中，改善 T 调节细胞反应可能会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为 ARDS 患者亚群制定个性化治疗策略。