Targeting Estrogenic pathways in Tregs to promote ARDS resolution

针对 Tregs 中的雌激素通路促进 ARDS 缓解

基本信息

批准号：
10632120
负责人：
Franco R D'Alessio
金额：
$ 80.98万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10632120
关键词：
Acute Acute Pneumonia Acute Respiratory Distress Syndrome Agonist Alveolar Animals Antiviral Response COVID-19 Candidate Disease Gene Cause of Death Cell Count Cell physiology Cells Cellular biology 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 Inflammatory Response Injury Lung Macrophage Mediating Mediator 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 vitro activity in vivo inflammatory lung disease loss of function lung injury mortality neutrophil novel therapeutics pathogen pneumonia model pneumonia treatment pre-clinical programs promoter repaired response therapeutic evaluation therapeutic target transcription factor

项目摘要

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）是全球死亡的主要原因之一。 PNA会导致急性急性急性呼吸窘迫综合征（ARDS）中肺部表现的炎症损伤。当前治疗 PNA专注于病原体，但不要靶向宿主免疫引起的多余的肺部感染回复。新感染的出现，均以COVID-19为代表，以及抗菌剂的不断增长的影响抗性病原体，突出我们当前的Armamentarium的局限性，并强调识别 PNA诱导的ARDS中的其他治疗靶标。认识到PNA的分辨率是积极监管的计划以促进恢复体内平衡，我们的工作致力于识别细胞和该分辨率阶段的分子介体。其他人，我们证明了调节性T细胞（Tregs）促进传染性标准的分辨率。我们强大的初步数据已经确定了肺衍生的Treg DHX58，该Treg DHX58编码RNA解旋酶蛋白对于抗病毒反应至关重要的，作为在ARDS分辨率阶段上调的候选基因。 DHX58- 不足的动物无法解决肺炎链球菌的肺部注射损伤分辨率期间的肺Treg数量减少，这意味着DHX58在体内的最佳Treg功能中。更远，我们观察到了假定的功能丧失变体的DHX58的载体中的30天死亡率显着增加具有传染性ARD（71％vs.47％，P = 0.01），强调了DHX58在ARDS中的潜在临床影响结果。我们对DHX58启动子的核内分析确定了许多雌激素反应元件（ERE）。实际上，雌二醇（E2）在Tregs中诱导了DHX58的表达。重要的是，我们发表的工作表明治疗性E2以Treg依赖性方式促进临床前PNA-dard的分辨率。雌激素受体β （er）对于Treg依赖淋巴细胞宿主的营救和Treg介导的抑制是必要的体外巨噬细胞中促炎性细胞因子的产生。初步基因表达分析和高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（TFS），特别是FOXP3和GATA3。这是我们假设E2，部分通过ER依赖性 DHX58的上调，通过钥匙的调节表达来协调关键的Treg促分辨率功能 treg中的TF。该提案的目标是确定细胞，分子和转录确定器在Treg介导的PNA标准分辨率中，E2-ER-DHX58的of提供了机械基础 ER在Tregs中的调节和功能作用。