Regulatory T cell Function in Pediatric Lung Injury

小儿肺损伤中的调节性 T 细胞功能

• 批准号: 8782734
• 负责人: Kevin Gibbs
• 金额: $ 5.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8782734
• 关键词: Accounting; Acute Lung Injury; Adolescent; Adoptive Transfer; Adult; Affect; Alveolar; Alveolus; Antibodies; Apoptosis; Attenuated; Biological Assay; Birth; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cell Proliferation; Cell physiology; Cells; Cessation of life; Chemotaxis; Child; Childhood; Complex; Data; Defect; Disease; Dose; Endotoxins; Enzyme-Linked Immunosorbent Assay; Fellowship; Fetal Tissues; Flow Cytometry; Genetic Transcription; Growth and Development function; Healthcare; Hypoxemia; IL2RA gene; Immune; Immune response; Immune system; In Vitro; Individual; Inflammation; Inflammatory; Injury; Instruction; Interleukin-2; Kinetics; Knowledge; Lead; Life; Lipopolysaccharides; Lung; Lymphocyte Subset; Lymphoid Tissue; Measures; Mediating; Mentors; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; National Research Service Awards; Neonatal; Newborn Infant; Outcome; Patients; Peripheral; Phenotype; Physicians; Play; Pneumonia; Population; Predisposition; Recombinant Interleukin-2; Recovery; Regulatory T-Lymphocyte; Research; Resolution; Respiratory Failure; Role; Scientist; Source; Spleen; Structure of parenchyma of lung; Supportive care; Termination of pregnancy; Therapeutic Intervention; Thymus Gland; Time; Titrations; Training; Umbilical Cord Blood; age related; career; clinically significant; falls; fetal; improved; in vivo; injured; insight; intraperitoneal; lung injury; migration; molecular phenotype; mortality; mouse model; neonatal lung injury; neonate; new therapeutic target; novel; novel therapeutics; prevent; public health relevance; research study; response; skills

DESCRIPTION (provided by applicant): The overall objective of this NRSA Individual Fellowship is to develop skills that will allow the candidate to become a physician-scientist and pursue an academic research career. The applicant and his mentors have devised a training approach that includes both research and didactic instruction. This approach will establish the knowledge and intellectual framework essential for a successful research career. The proposal concerns acute lung injury (ALI) in neonates and juveniles. Pediatric acute lung injury represents a major global source of morbidity and mortality. Pneumonia-associated ALI in neonates accounts for 10% of annual childhood deaths. Despite the healthcare burden associated with this disease, the mechanisms through which pediatric ALI resolves remain unknown. Regulatory T cells (Tregs), a subset of cells in the adaptive immune system that suppresses exuberant immune responses, have been shown to play a critical role in lung injury resolution in an adult mouse endotoxin (LPS) model of ALI. There is, however, little data on the role and function of Tregs in pediatric ALI. Tregs play an important role in fetal life by suppressing auto-reactive immune cells and preventing inflammation that may lead to fetal loss; however, these cells may be functionally impaired in the newborn as the immune system transitions from a tolerant state to a pro-inflammatory one. The candidate has preliminary data showing in neonates, unlike in juvenile mice, alveolar Treg numbers do not increase following LPS- mediated lung injury. Increasing Treg number by adoptive transfer enhances resolution and restores normal growth and development in LPS-injured neonates. The focus of this proposal is to further examine the factors that contribute to the diminished Treg response in neonates with the long term hope of discovering novel therapeutic targets for children with ALI. In Specific Aim 1, the candidate will examine the differences in the Treg response of neonatal and juvenile mice following lung injury. Multicolor flow cytometry will be used to determine Treg kinetics and phenotype. Adoptive Transfer of neonatal Tregs into Treg-depleted adults and suppression assays will measure in vivo and ex vivo Treg function. Specific Aim 2 will define the IL-2/CD25 axis modulation of the neonatal Treg response. The candidate will determine age-dependent IL-2 expression by real time PCR and ELISA. He will also define the ability of exogenous IL-2 administration to expand Treg numbers, increase suppressive function, and enhance acute lung injury resolution. These experiments will explore the mechanisms controlling neonatal Treg function following acute lung injury with the ultimate hope of improving patient outcomes in this lethal disease.

描述（由申请人提供）：该NRSA个人奖学金的总体目标是发展技能，使候选人成为医师科学家并从事学术研究职业。申请人及其导师设计了一种培训方法，其中包括研究和教学教学。这种方法将建立成功研究职业必不可少的知识和知识框架。该提案涉及新生儿和少年的急性肺损伤（ALI）。小儿急性肺损伤代表了全球发病率和死亡率的主要来源。肺炎与新生儿相关的ALI占儿童死亡人数的10％。尽管与这种疾病相关的医疗保健负担，但小儿阿里解决的机制仍然未知。 调节性T细胞（Tregs）是抑制繁殖免疫反应的自适应免疫系统中细胞的子集，已显示在ALI的成年小鼠内毒素（LPS）模型中起关键作用。但是，关于Treg在小儿ALI中的作用和功能的数据很少。 Tregs通过抑制自身反应性免疫细胞并防止炎症可能导致胎儿丧失，在胎儿生活中发挥重要作用。但是，这些细胞在新生儿的功能上可能会受到损害，因为免疫系统从耐受状态转变为促炎性状态。该候选人在新生儿中显示了初步数据，与少年小鼠不同，LPS介导的肺损伤后肺泡数量不会增加。通过收养转移增加TREG数量可以增强分辨率，并恢复LPS损害的新生儿的正常生长和发展。该提案的重点是进一步研究新生儿中Treg反应减少的因素，长期希望为ALI儿童发现新的治疗靶点。 在特定的目标1中，候选人将检查肺损伤后新生儿和少年小鼠的Treg反应的差异。多色流式细胞仪将用于确定Treg动力学和表型。新生儿Tregs的收养转移到贫困的成年人中，抑制测定将测量体内和离体Treg功能。特定的目标2将定义新生儿Treg响应的IL-2/CD25轴调节。候选人将通过实时PCR和ELISA确定年龄依赖性的IL-2表达。他还将定义外源性IL-2给药扩大TREG数量，增加抑制功能并增强急性肺损伤的能力。这些实验将探索急性肺损伤后控制新生儿Treg功能的机制，并最终希望改善这种致命疾病的患者结局。