Pathobiology of MRSA-induced Endothelial Permeability and Acute Lung Injury

MRSA 诱导的内皮通透性和急性肺损伤的病理学

基本信息

  • 批准号:
    10608606
  • 负责人:
  • 金额:
    $ 65.27万
  • 依托单位:
  • 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:
    2022-12-20 至 2026-11-30
  • 项目状态:
    未结题

项目摘要

SUMMARY: Despite decades of targeted research, no effective pharmacologic interventions have been identified for the Acute Respiratory Distress Syndrome (ARDS), which is a life-threatening disease process characterized by dysregulated immune responses. Sepsis is a major cause of ARDS, and the pathophysiology of both processes is characterized by alterations in microcirculatory blood flow, with vascular endothelial cell (EC) dysfunction playing a major role in organ injury. Novel mechanistic insights are needed to assist the development of therapies to address the EC barrier dysfunction that underlies ARDS and sepsis. Staphylococcus (S.) aureus is a frequently identified organism in gram-positive sepsis, and the highly virulent, antibiotic-resistant methicillin-resistant S. aureus (MRSA) strain is particularly challenging to treat and a major cause of ARDS. Important knowledge gaps exist both in MRSA-induced pathophysiology relevant to ARDS and in the mechanistic understanding of EC-specific processes that can be targeted therapeutically. Endogenous sphingosine-1-phosphate (S1P) and the structurally similar pharmaceutical compound, FTY720 (FTY), have EC barrier-enhancing effects in preclinical models of ARDS. However, both S1P and FTY also induce a myriad of other effects that are potentially harmful in critically ill patients and make them poor therapeutic candidates. We therefore have explored the barrier-regulatory properties of novel FTY720 analogs to better understand how these compounds regulate permeability. Our work has revealed that FTY720 (S)- phosphonate (Tys) has superior efficacy in several preclinical models and maintains expression levels of the essential S1PR1 receptor, unlike other agonists which induce its degradation. In addition, epigenetic processes are increasingly being recognized as important pathogenic steps during inflammatory acute lung injury (ALI)/ARDS and sepsis, and epigenetic responses (such as histone acetylation) can be altered by S1P-related signaling. Our central hypothesis is that MRSA causes EC dysfunction relevant to ARDS by epigenetic and other pathophysiologic mechanisms that can be targeted by Tys/S1PR1-related signaling. Using ChIP-seq analysis and other epigenetic tools, we have generated new insights that MRSA triggers histone acetylation in lung EC to regulate genes involved in lung EC dysfunction. Exciting new data suggest Tys-S1PR1 signaling may ameliorate key aspects of these epigenetic effects. Aim #1 will determine the mechanisms by which Tys/S1PR1 signaling protects against MRSA-induced lung EC barrier disruption in vitro. Aim #2 will use state- of-the-art ChIP-seq and other approaches to characterize novel MRSA- and Tys/S1PR1-induced epigenetic changes that have functional consequences in lung EC, including the novel MRSA target identified by our epigenetic screening, CYP1A1. Aim #3 will extend these studies in vivo by characterizing epigenetic and other mechanisms of MRSA-induced lung injury in mice and determine the efficacy of Tys. Overall, these studies will advance our mechanistic understanding of MRSA-induced ARDS to identify novel therapeutic targets.
摘要: 尽管进行了几十年的有针对性的研究,但尚未发现有效的药物干预措施。 急性呼吸窘迫综合征(ARDS)是一种危及生命的疾病过程,其特征是 免疫反应失调。脓毒症是ARDS的主要原因,两者的病理生理学 过程的特点是微循环血流的改变,血管内皮细胞(EC) 功能障碍在器官损伤中起主要作用。需要新的机械洞察力来帮助 开发治疗方法来解决导致ARDS和脓毒症的EC屏障功能障碍。 葡萄球菌(S.)金黄色葡萄球菌是革兰氏阳性败血症中常见的一种微生物, 耐甲氧西林金黄色葡萄球菌(MRSA)菌株的治疗尤其具有挑战性,也是一种主要的 导致急性呼吸窘迫综合征。在MRSA诱导的与ARDS相关的病理生理学方面存在重要的知识空白 以及对EC特定过程的机械性理解,这些过程可以作为治疗的靶点。 内源性鞘氨醇-1-磷酸(S1P)和结构相似的药物化合物FTY720 (FTY),在ARDS的临床前模型中具有EC屏障增强作用。然而,S1P和FTY也 引发无数其他对危重病人有潜在危害的影响,使他们变得贫穷 治疗候选人。因此,我们探索了新型FTY720类似物的屏障调节特性 为了更好地了解这些化合物是如何调节通透性的。我们的工作揭示了FTY720(S)- 磷酸盐(Tys)在几种临床前模型中具有优越的疗效,并保持了 必需的S1PR1受体,不同于其他导致其降解的激动剂。此外,表观遗传过程 越来越被认为是炎症性急性肺损伤的重要致病步骤 (ALI)/ARDS和脓毒症,以及表观遗传反应(如组蛋白乙酰化)可以通过S1P相关的方式改变 发信号。我们的中心假设是,MRSA通过表观遗传和基因突变导致与ARDS相关的EC功能障碍 Tys/S1PR1相关信号可能针对的其他病理生理机制。使用Chip-seq 分析和其他表观遗传学工具,我们已经产生了新的见解,MRSA触发组蛋白乙酰化在 肺内皮细胞调节参与肺内皮细胞功能障碍的基因。令人兴奋的新数据表明Tys-S1PR1信号 可能会改善这些表观遗传效应的关键方面。目标1将确定通过哪些机制 TYS/S1PR1信号通路对MRSA诱导的肺内皮细胞屏障破坏的保护作用目标2将使用状态- 用最先进的芯片序列和其他方法表征MRSA和Tys/S1PR1诱导的表观遗传学 在肺EC中具有功能后果的变化,包括我们的研究确定的新的MRSA靶点 表观遗传学筛查,细胞色素P1A1。目标#3将通过表征表观遗传学和其他方面在体内扩展这些研究 耐甲氧西林金黄色葡萄球菌致小鼠肺损伤的机制及TYS的疗效观察总体而言,这些研究将 促进我们对MRSA诱导的ARDS的机制的理解,以确定新的治疗靶点。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

STEVEN M DUDEK其他文献

STEVEN M DUDEK的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('STEVEN M DUDEK', 18)}}的其他基金

Patient Sampling and Genomics Core
患者采样和基因组学核心
  • 批准号:
    10701927
  • 财政年份:
    2021
  • 资助金额:
    $ 65.27万
  • 项目类别:
Patient Sampling and Genomics Core
患者采样和基因组学核心
  • 批准号:
    10491060
  • 财政年份:
    2021
  • 资助金额:
    $ 65.27万
  • 项目类别:
Fostering Academic Physician-Investigators Treating High Risk Populations
培养治疗高危人群的学术医师研究人员
  • 批准号:
    10647841
  • 财政年份:
    2021
  • 资助金额:
    $ 65.27万
  • 项目类别:
Fostering Academic Physician-Investigators Treating High Risk Populations
培养治疗高危人群的学术医师研究人员
  • 批准号:
    10459247
  • 财政年份:
    2021
  • 资助金额:
    $ 65.27万
  • 项目类别:
Patient Sampling and Genomics Core
患者采样和基因组学核心
  • 批准号:
    10170862
  • 财政年份:
    2021
  • 资助金额:
    $ 65.27万
  • 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
  • 批准号:
    10472480
  • 财政年份:
    2019
  • 资助金额:
    $ 65.27万
  • 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
  • 批准号:
    10700843
  • 财政年份:
    2019
  • 资助金额:
    $ 65.27万
  • 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
  • 批准号:
    9791769
  • 财政年份:
    2019
  • 资助金额:
    $ 65.27万
  • 项目类别:
Postdoctoral Training Program in Pulmonary and Critical Care Translational Research
肺部和重症监护转化研究博士后培训项目
  • 批准号:
    10198029
  • 财政年份:
    2019
  • 资助金额:
    $ 65.27万
  • 项目类别:
Crosstalk between S1P Receptor 1/S1P1 and P-Selectin/Selp in Regulation of Inflammatory Vascular Permeability
S1P 受体 1/S1P1 和 P-选择素/Selp 之间的串扰调节炎症血管通透性
  • 批准号:
    10871784
  • 财政年份:
    2016
  • 资助金额:
    $ 65.27万
  • 项目类别:

相似海外基金

Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
  • 批准号:
    EP/Y003527/1
  • 财政年份:
    2024
  • 资助金额:
    $ 65.27万
  • 项目类别:
    Research Grant
The Association Between Aging, Inflammation, and Clinical Outcomes in Acute Respiratory Distress Syndrome
衰老、炎症与急性呼吸窘迫综合征临床结果之间的关联
  • 批准号:
    10722669
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
Sedatives Pharmacology in Acute Respiratory Distress Syndrome- SPA
急性呼吸窘迫综合征中的镇静药理学 - SPA
  • 批准号:
    491387
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
    Fellowship Programs
New mechanism-based TREM-1 therapy for acute respiratory distress syndrome
基于新机制的 TREM-1 疗法治疗急性呼吸窘迫综合征
  • 批准号:
    10678788
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
Great Lakes Clinical Center of the Acute Respiratory Distress Syndrome, Pneumonia and Sepsis (APS) Consortium
急性呼吸窘迫综合征、肺炎和败血症 (APS) 联盟五大湖临床中心
  • 批准号:
    10646578
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
Effect of ADAMTS13 on pathogenesis of acute respiratory distress syndrome
ADAMTS13 对急性呼吸窘迫综合征发病机制的影响
  • 批准号:
    23K08447
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A Novel Synthetic Biology-Derived Microbiome Therapeutic to Treat Viral-Induced Acute Respiratory Distress Syndrome (ARDS)
一种新型合成生物学衍生的微生物疗法,可治疗病毒引起的急性呼吸窘迫综合征(ARDS)
  • 批准号:
    10601865
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
Development of drug therapy targeting ferroptosis, iron-dependent cell death for acute respiratory distress syndrome.
开发针对铁死亡(急性呼吸窘迫综合征的铁依赖性细胞死亡)的药物疗法。
  • 批准号:
    23K08360
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Sustainable Implementation of Prone Positioning for the Acute Respiratory Distress Syndrome
持续实施俯卧位治疗急性呼吸窘迫综合征
  • 批准号:
    10722194
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
Point-of-care system to assess the risk of trauma-induced acute respiratory distress syndrome
用于评估创伤引起的急性呼吸窘迫综合征风险的护理点系统
  • 批准号:
    10594793
  • 财政年份:
    2023
  • 资助金额:
    $ 65.27万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了