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）是全球主要的死亡原因之一。PNA可导致毁灭性的急性 肺中的炎性损伤表现为急性呼吸窘迫综合征（ARDS）。的当前治疗 PNA主要针对病原体，但不针对宿主免疫引起的过度肺部炎症 反应以COVID-19为代表的新感染的出现，以及抗菌药物的影响不断扩大， 耐药病原体，突出了我们目前医疗设备的局限性，并强调需要确定 PNA诱导的ARDS的其他治疗靶点。应当理解，PNA的分辨率是 积极调节程序，以促进恢复稳态，我们的工作集中在确定细胞和 分子介导的这个解决阶段。其他人和我们已经证明，调节性T细胞（T细胞） 促进感染性ARDS的消退。 我们强有力的初步数据已经鉴定了肺源性Treg DHX 58，其编码RNA解旋酶蛋白 抗病毒反应所必需的，作为候选基因在ARDS的解决阶段上调。公司简介 缺陷型动物在肺炎链球菌-ARDS后不能解决肺部炎症， 在损伤消退期间减少肺Treg数量，暗示DHX 58在体内最佳Treg功能中。此外，本发明还 我们观察到DHX 58的假定功能丧失变异体携带者的30天死亡率显著增加 感染性ARDS（71% vs. 47%，p=0.01），强调了DHX 58在ARDS中的潜在临床影响 结果。我们对DHX 58启动子的计算机分析鉴定了许多雌激素反应元件（ERE）。 事实上，DHX 58的表达是由雌二醇（E2）诱导的。重要的是，我们发表的研究表明， 治疗性E2以Treg依赖性方式促进临床前PNA-ARDS的消退。雌激素受体β (ER对于Treg依赖性的淋巴细胞减少宿主的拯救和Treg介导的对淋巴细胞减少的抑制都是必需的。 体外巨噬细胞中促炎细胞因子的产生。初步基因表达分析和高- 三维流式细胞术表明E2及其下游靶点DHX 58参与调节关键性Treg 转录因子（TF），特别是Foxp 3和GATA 3。因此，我们假设E2，部分通过ER β依赖性， DHX 58的上调，通过调节关键的调节因子的表达，协调关键的Treg促消退功能， 在Tibet中的TF。这个建议的目标是确定细胞，分子和转录决定因素 E2-ER β-DHX 58在Treg介导的PNA-ARDS消退中的作用，以提供E2-ER β-DHX 58在PNA-ARDS消退中的机制基础。 ER β在THP中的调节和功能作用。