Regulatory T cell Function in Pediatric Lung Injury

小儿肺损伤中的调节性 T 细胞功能

基本信息

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
项目类别：
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

项目摘要

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培养技能，使候选人能够成为一名医师科学家并从事学术研究职业。申请人和他的导师设计了一种培训方法，包括研究和教学指导。这种方法将建立成功的研究生涯所必需的知识和智力框架。该提案涉及新生儿和青少年的急性肺损伤（ALI）。儿童急性肺损伤是全球发病率和死亡率的一个主要来源。新生儿肺炎相关的 ALI 占每年儿童死亡人数的 10%。尽管这种疾病会造成医疗负担，但小儿 ALI 的解决机制仍不清楚。调节性 T 细胞 (Treg) 是适应性免疫系统中抑制旺盛免疫反应的细胞子集，已被证明在成年小鼠内毒素 (LPS) ALI 模型中的肺损伤缓解中发挥着关键作用。然而，关于 Tregs 在儿科 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预防可能导致胎儿流产的炎症，在胎儿生命中发挥着重要作用；然而，随着免疫系统从耐受状态转变为促炎状态，这些细胞在新生儿中可能会功能受损。该候选者的初步数据显示，与幼年小鼠不同，新生儿的肺泡 Treg 数量在 LPS 介导的肺损伤后不会增加。通过过继转移增加 Treg 数量可增强 LPS 损伤新生儿的分辨率并恢复正常生长和发育。该提案的重点是进一步研究导致新生儿 Treg 反应减弱的因素，长期希望为 ALI 儿童发现新的治疗靶点。在具体目标 1 中，考生将检查肺损伤后新生小鼠和幼年小鼠 Treg 反应的差异。多色流式细胞术将用于确定 Treg 动力学和表型。将新生儿 Treg 过继转移至 Treg 耗尽的成人中并进行抑制测定，将测量体内和离体 Treg 功能。具体目标 2 将定义新生儿 Treg 反应的 IL-2/CD25 轴调节。候选人将通过实时 PCR 和 ELISA 确定年龄依赖性 IL-2 表达。他还将定义外源性 IL-2 给药扩大 Treg 数量、增强抑制功能和增强急性肺损伤缓解的能力。这些实验将探索急性肺损伤后控制新生儿 Treg 功能的机制，最终希望改善这种致命疾病的患者预后。