Mechanisms and Treatment of SARS-CoV-2 induced Lung Endothelial Injury

SARS-CoV-2引起的肺内皮损伤的机制和治疗

• 批准号: 10559640
• 负责人: Asrar B. Malik
• 金额: $ 73.9万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559640
• 关键词: 2019-nCoV; ACE2; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adherens Junction; Affinity; Binding; Binding Proteins; Biological Response Modifiers; Blood Vessels; COVID-19; COVID-19 pandemic; COVID-19 severity; COVID-19 treatment; Categories; Cell Reprogramming; Cells; Cessation of life; Complement; Complication; Data; Development; Disease; Down-Regulation; Edema; Elements; Endothelial Cells; Endothelium; Engineering; Epithelial Cells; Epithelium; Functional disorder; Genetic; Host Defense; Human; Immune; Immune response; Immune system; Inflammasome; Inflammatory; Inflammatory Response; Injury; Interferon Type I; Interleukin-1 beta; Interleukin-6; Intravenous; K-18 conjugate; Knowledge; Liquid substance; Lung; Mediating; Mus; Nature; Pathogenicity; Patients; Peptide Hydrolases; Peptides; Permeability; Phase; Predisposition; Proteins; Research; Role; Route; SARS-CoV-2 spike protein; SARS-CoV-2 variant; Signal Transduction; Syndrome; TMPRSS2 gene; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; United States; Vaccination; Vaccines; Variant; Vascular Permeabilities; Viral; Viral Antigens; Virus; anakinra; antagonist; cadherin 5; cell injury; cell type; cellular engineering; cytokine; cytokine release syndrome; endothelial regeneration; humanized mouse; lung injury; lung vascular injury; mortality; mouse model; novel therapeutics; pharmacologic; prevent; receptor; response; severe COVID-19; severe injury; single-cell RNA sequencing; therapeutic target; tissue injury; uptake; vaccine access; vaccine response; variants of concern

PROJECT SUMMARY / ABSTRACT Coronavirus disease 2019 (COVID-19) is a devastating systemic inflammatory syndrome caused by the coronavirus SARS-CoV-2 which has resulted in over 500,000 deaths in the US during the past year, with this high rate of mortality being attributed in large part to the development of Acute Lung Injury (ALI) or Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 entry into cells requires the direct binding of the SARS-CoV-2 spike (S)-protein to the principal host protease-TMPRSS2 and the angiotensin converting enzyme 2 (ACE-2) receptors which are expressed in multiple host cell types. The development of efficacious vaccines to prevent the spread of SARS-CoV-2 represents a tremendous advance that will help curb the COVID-19 pandemic, however the emergence of variants of concern such as the B1.1.7, P1 and B1.351 which can evade the neutralizing responses of the vaccine-induced humoral immune response underscores the urgent need to develop novel therapeutics to complement the vaccination efforts. Based on our provocative Supporting Data, we have formulated the overarching hypothesis that SARS-CoV-2 induced lung endothelial injury is a requisite element of COVID-19 induced maladaptive inflammatory injury that can be therapeutically targeted. We propose the following specific aims: In Aim 1, we will define the nature and underlying mechanisms of lung endothelial injury underlying COVID-19-induced ALI/ARDS. We will test the hypothesis that the degree of lung endothelial injury is a key determinant of the overall pathogenicity and mortality of multiple SARS- CoV-2 variants. We will establish SARS-CoV-2-induced lung vascular injury and compensatory lung endothelial regeneration using two complementary humanized ACE2 mouse models, EC-specific genetic lineage tracing, genetic stabilization of VE-cadherin and single cell RNA-Sequencing. In Aim 2, we will define the efficacy and optimal temporal windows for two targeted pharmacological therapeutic strategies in preventing and resolving SARS-CoV- 2 induced lung endothelial injury. We will test the hypothesis that an engineered soluble hACE-2 peptide has a higher therapeutic efficacy than the wildtype hACE-2 peptide in reducing lung endothelial injury as well as long-term EC reprogramming by preventing viral entry and dissemination of multiple SARS-CoV-2 variants. We will test the corollary hypothesis and that targeted inhibition of IL1β-signaling using a modified IL-1 Receptor antagonist is protective against the feed-forward inflammatory loop and endothelial injury induced by multiple SARS-CoV2 variants. We will use two hACE-2 mouse models as well as compare distinct routes of delivery (intratracheal versus intravenous) and identify the optimal temporal windows for the therapeutic intervention.

项目概要/摘要 2019 年冠状病毒病 (COVID-19) 是一种由冠状病毒引起的破坏性全身炎症综合征 SARS-CoV-2 在过去一年已导致美国超过 50 万人死亡，死亡率如此之高 很大程度上归因于急性肺损伤 (ALI) 或急性呼吸窘迫综合征 （ARDS）。 SARS-CoV-2 进入细胞需要 SARS-CoV-2 刺突 (S) 蛋白与主要蛋白直接结合 宿主蛋白酶 TMPRSS2 和血管紧张素转换酶 2 (ACE-2) 受体表达于 多种宿主细胞类型。开发有效的疫苗来预防 SARS-CoV-2 的传播意味着 这是一项巨大的进步，将有助于遏制 COVID-19 大流行，但令人担忧的变种的出现 例如B1.1.7、P1和B1.351，它们可以逃避疫苗诱导的体液中和反应 免疫反应强调迫切需要开发新的疗法来补充疫苗接种工作。 根据我们具有争议性的支持数据，我们制定了总体假设，即 SARS-CoV-2 诱导的肺内皮损伤是 COVID-19 诱导的适应不良炎症损伤的必要因素， 成为治疗目标。我们提出以下具体目标： 在目标 1 中，我们将定义本质和基础 COVID-19 诱导的 ALI/ARDS 的肺内皮损伤机制。我们将检验以下假设： 肺内皮损伤程度是多种 SARS 总体致病性和死亡率的关键决定因素 CoV-2 变种。我们将建立SARS-CoV-2诱导的肺血管损伤和代偿性肺内皮细胞 使用两种互补的人源化 ACE2 小鼠模型进行再生，EC 特异性遗传谱系追踪， VE-钙粘蛋白的遗传稳定性和单细胞 RNA 测序。在目标 2 中，我们将定义功效和最佳 预防和解决 SARS-CoV 的两种靶向药物治疗策略的时间窗口 2诱发肺内皮损伤。我们将检验以下假设：工程化的可溶性 hACE-2 肽具有 与野生型 hACE-2 肽相比，在减轻肺内皮损伤以及长期治疗方面具有更高的治疗效果 通过防止病毒进入和传播多种 SARS-CoV-2 变体来进行 EC 重编程。我们将测试 推论假设，并且使用修饰的 IL-1 受体拮抗剂靶向抑制 IL1β 信号传导是 防止多种 SARS-CoV2 诱导的前馈炎症循环和内皮损伤 变种。我们将使用两种 hACE-2 小鼠模型并比较不同的递送途径（气管内与 静脉注射）并确定治疗干预的最佳时间窗口。