Targeting Estrogenic pathways in Tregs to promote ARDS resolution

针对 Tregs 中的雌激素通路促进 ARDS 缓解

• 批准号: 10462918
• 负责人: Franco R D'Alessio
• 金额: $ 81.63万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462918
• 关键词: Acute; Acute Pneumonia; Acute Respiratory Distress Syndrome; Agonist; Alveolar; Animals; Antiviral Response; Biology; COVID-19; Candidate Disease Gene; Cause of Death; Cells; Clinical; Clinical Trials; Critical Pathways; Data; Development; Disease model; Elements; Estradiol; Estrogen Receptor beta; Estrogens; FOXP3 gene; Flow Cytometry; GATA3 gene; Gene Expression; Gene Expression Profiling; Genetic Transcription; Goals; Homeostasis; Human; Immune; Immune response; In Vitro; Infection; Inflammatory; Injury; Lung; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Outcome; Pathogenicity; Pathway interactions; Phase; Pilot Projects; Play; Pneumonia; Pre-Clinical Model; Production; Proteins; Publishing; Pulmonary Inflammation; RNA Helicase; Regulation; Regulatory T-Lymphocyte; Resolution; Role; Signal Pathway; Signal Transduction; Streptococcus pneumoniae; Testing; Therapeutic; Therapeutic Effect; Up-Regulation; Variant; Work; acute infection; alveolar epithelium; antimicrobial resistant pathogen; cytokine; drug resistant pathogen; estrogenic; high dimensionality; in silico; in vivo; inflammatory lung disease; loss of function; lung injury; macrophage; mortality; neutrophil; novel therapeutics; pathogen; pneumonia model; pneumonia treatment; pre-clinical; programs; promoter; repaired; response; therapeutic evaluation; therapeutic target; transcription factor

Pneumonia (PNA) is one of the leading causes of death worldwide. PNA can result in devastating acute inflammatory injury in the lung manifesting in acute respiratory distress syndrome (ARDS). Current treatments for PNA have focused on the pathogens, but do not target excessive lung inflammation elicited by the host immune response. Both the emergence of new infections, typified by COVID-19, and the expanding impact of antimicrobial resistant pathogens, highlight the limitations of our current armamentarium and underscore the need to identify additional therapeutic targets in PNA-induced ARDS. With the understanding that resolution of PNA is an actively regulated program to promote return to homeostasis, our work has focused on identifying cellular and molecular mediators of this resolution phase. Others and we have demonstrated that regulatory T cells (Tregs) promote resolution of infectious-ARDS. Our strong preliminary data has identified lung-derived Treg DHX58, which encodes an RNA helicase protein essential for antiviral responses, as a candidate gene upregulated during the resolution phase of ARDS. DHX58- deficient animals fail to resolve lung inflammation after Streptococcus pneumoniae-ARDS with significantly diminished lung Treg numbers during injury resolution, implicating DHX58 in optimal Treg function in vivo. Further, we observed significantly increased 30-day mortality among carriers of a putative loss-of-function variant of DHX58 with infectious ARDS (71% vs. 47%, p=0.01), underscoring the potential clinical impact of DHX58 in ARDS outcomes. Our in-silico analysis of the DHX58 promoter identified numerous estrogen responsive elements (ERE). Indeed, DHX58 expression was induced in Tregs by estradiol (E2). Importantly, our published work showed that therapeutic E2 promotes resolution of preclinical PNA-ARDS in a Treg-dependent manner. Estrogen receptor beta (ER) was necessary for both Treg-dependent rescue of lymphopenic hosts and Treg-mediated suppression of pro-inflammatory cytokine production in macrophages in vitro. Preliminary gene expression analysis and high- dimensional flow cytometry implicate E2 and its downstream-target, DHX58, in the regulation of critical Treg transcription factors (TFs), notably Foxp3 and GATA3. Thus, we hypothesize that E2, in part via ER-dependent upregulation of DHX58, orchestrates critical Treg pro-resolution functions, through regulating expression of key TFs in Tregs. The goals of this proposal are to determine the cellular, molecular and transcriptional determinants of E2-ER-DHX58 in Treg-mediated resolution of PNA-ARDS to provide the mechanistic underpinnings of the regulation and functional role of ER in Tregs.

肺炎（PNA）是全球死亡世界的主要原因之一。 急性呼吸窘迫综合征（ARDS）的肺部炎症损伤 PNA专注于病原体，但不要靶向宿主免疫引起的过度肺部炎症 反应。 抗性病原体，突出了我们当前的Armamentarium Anderscore的局限性 PNA诱导的ARDS中的其他治疗方法，理解PNA的分辨率为AN。 积极的重复计划以促进恢复体内平衡，我们的工作重点是识别细胞和 该分辨率阶段的分子介体。 促进传染性标准的分辨率。 我们的强大预选 抗病毒反应必不可少的 不足的动物无法解决肺炎链球菌的肺部炎症 损伤分辨率期间的肺Treg数量减少，在体内最佳Treg功能中刺激了DHX58。 我们观察到的 感染学ARDS（71％vs。47％，P = 0.01），强调了DHX58在ARDS中的潜在临床影响 结果。 实际上，雌二醇在Treg中诱导了DHX58（E2）。 治疗性E2促进了以Treg依赖性方式的临床前PNA-pard分辨率 （er）对于Treg依赖性营救淋巴细胞宿主和Treg介导的抑制都是必要的 巨噬细胞中的促炎细胞因子的体外基因表达分析。 尺寸流式细胞术暗示E2及其下游目标DHX58在临界Treg的调节中 转录因子（TF），特别是Foxp3和Gata3。 DHX58的上调，策划了关键的Treg促分辨率功能，尽管调节了密钥的表达。 Treg中的TF。 在Treg介导的PNA-pard分辨率中，Of-e2-er-dhx58提供了机械基础 ER在Tregs中的调节和功能作用。