Regulatory T cells and Inflammatory Injury of the Developing Murine Lungs

调节性 T 细胞和小鼠肺发育中的炎症损伤

基本信息

批准号：
10368051
负责人：
Binoy Shivanna
金额：
$ 8万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-08 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368051
关键词：
Address Adoptive Transfer Alveolar Area Attenuated Blood Vessels Bronchopulmonary Dysplasia CCR5 gene Chronic Chronic lung disease Data Development Diphtheria Toxin Disease Economic Burden Escherichia coli Exposure to FOXP3 gene Female Functional disorder Goals Green Fluorescent Proteins Homeostasis Hospital Costs Human Immune Infant Infection Inflammation Inflammatory Injury Interruption Intervention Knowledge Lead Life Lipopolysaccharides Lung Lung diseases Lymphocyte Mediating Molecular Morbidity - disease rate Mouse Protein Mus Necrotizing Enterocolitis Neonatal Pathogenesis Patients Periventricular Leukomalacia Phase Premature Infant Premature Infant Diseases Pulmonary Inflammation RAG1 gene RANTES Rag1 Mouse Regulatory T-Lymphocyte Research Resolution Retinopathy of Prematurity Role Secondary to Sepsis Severities Signal Transduction Structure of parenchyma of lung Testing Tissues Transgenic Mice Vascular Diseases Wild Type Mouse base chemokine receptor curative treatments design diphtheria toxin receptor genetic approach immunomodulatory therapies infancy injury and repair innovation insight lung development lung injury lung vascular injury male mature animal mouse model multidisciplinary mutant neonatal lung injury neonatal mice novel prevent recruit targeted treatment therapeutic target

项目摘要

Abstract/Summary Bronchopulmonary dysplasia (BPD) is the most common chronic infantile lung disease that lacks curative therapies. Further, BPD increases the economic burden and long-term morbidities in preterm infants. Sepsis-mediated persistent lung inflammation is central to the pathogenesis of BPD, which is characterized by interrupted lung development, i.e., alveolar simplification. However, the molecular mechanisms that modulate neonatal lung inflammation are poorly understood. Regulatory T cells (Tregs) are crucial to maintain immune homeostasis and prevent tissue damage. Further, they promote resolution of lung inflammation and injury in adult animals; however, the role of Tregs in BPD pathogenesis remains unclear. Additionally, the mechanisms of Treg recruitment in neonatal lungs are poorly studied. So, we propose to address these knowledge gaps using a neonatal mouse model of lipopolysaccharide (LPS)-induced chronic inflammatory lung injury. Our preliminary studies in neonatal mice indicate that: (1) LPS decreases Tregs and their C-C motif chemokine receptor 5 (CCR5) expression in lungs; and (2) Treg depletion induces inflammation and potentiates LPS- mediated lung injury. Based on our novel data, we will test the central hypothesis that Tregs are necessary and sufficient to protect against LPS-induced inflammatory lung injury in neonatal mice. We will use a unique combination of molecular, cellular, and functional approaches to test this hypothesis. In Aim 1, we will use transgenic mice to determine if Tregs are necessary and sufficient to protect neonatal mice against LPS- induced lung and pulmonary vascular injury and dysfunction. In Aim 2, we will use transgenic mice to examine the mechanisms of lung Treg recruitment. We expect that successful completion of these studies would provide a mechanistic rationale for targeting Tregs to develop meaningful therapies for BPD infants. Our studies also could positively impact other inflammation-related neonatal research areas, including necrotizing enterocolitis, retinopathy of prematurity, and periventricular leukomalacia.

摘要/总结支气管肺发育不良（BPD）是最常见的慢性婴儿肺部疾病，缺乏治疗方法。此外，BPD 还增加了早产儿的经济负担和长期发病率。脓毒症介导的持续性肺部炎症是 BPD 发病机制的核心，其特点是肺部发育中断，即肺泡简化。然而，调节的分子机制人们对新生儿肺部炎症知之甚少。调节性 T 细胞 (Treg) 对于维持免疫至关重要体内平衡并防止组织损伤。此外，它们还促进肺部炎症和损伤的解决成年动物；然而，Tregs 在 BPD 发病机制中的作用仍不清楚。此外，机制新生儿肺部 Treg 募集的研究很少。因此，我们建议解决这些知识差距使用脂多糖（LPS）诱导的慢性炎症性肺损伤的新生小鼠模型。我们的在新生小鼠中的初步研究表明：（1）LPS 降低 Tregs 及其 C-C 基序趋化因子肺部受体 5 (CCR5) 表达； (2) Treg 耗竭会诱发炎症并增强 LPS- 介导的肺损伤。根据我们的新数据，我们将检验 Treg 的必要性和中心假设足以预防新生小鼠免受 LPS 诱导的炎症性肺损伤。我们将使用独特的结合分子、细胞和功能方法来检验这一假设。在目标 1 中，我们将使用转基因小鼠以确定 Tregs 是否必要且足以保护新生小鼠免受 LPS- 诱发肺及肺血管损伤和功能障碍。在目标 2 中，我们将使用转基因小鼠来检查肺 Treg 募集机制。我们期望这些研究的成功完成为针对 Tregs 为 BPD 婴儿开发有意义的疗法提供了机制原理。我们的研究还可能对其他与炎症相关的新生儿研究领域产生积极影响，包括坏死性小肠结肠炎、早产儿视网膜病和脑室周围白质软化症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ventilation-Induced Lung Injury (VILI) in Neonates: Evidence-Based Concepts and Lung-Protective Strategies.

DOI：
10.3390/jcm11030557
发表时间：
2022-01-22
期刊：
Journal of clinical medicine
影响因子：
3.9
作者：
Kalikkot Thekkeveedu R;El-Saie A;Prakash V;Katakam L;Shivanna B
通讯作者：
Shivanna B

Amphiregulin Exerts Proangiogenic Effects in Developing Murine Lungs.

DOI：
10.3390/antiox13010078
发表时间：
2024-01-08
期刊：
ANTIOXIDANTS
影响因子：
7
作者：
Thapa, Shyam;Shankar, Nithyapriya;Shrestha, Amrit Kumar;Civunigunta, Monish;Gaikwad, Amos S.;Shivanna, Binoy;Liu, Jiankang
通讯作者：
Liu, Jiankang