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: 10390863
• 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/10390863
• 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; Cells; Cessation of life; Complement; Complication; Coronavirus; Data; Development; Disease; Down-Regulation; Edema; Elements; Endothelial Cells; Endothelium; Engineering; Epithelial; Epithelial Cells; 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; Pharmacology; Phase; 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; base; 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; 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.

项目摘要 /摘要 2019年冠状病毒病（COVID-19）是由冠状病毒引起的毁灭性的全身性炎症综合征 SARS-COV-2在过去一年中导致美国超过500,000人死亡，死亡率很高 很大程度上归因于急性肺损伤（ALI）或急性呼吸窘迫综合征的发展 （ARDS）。 SARS-COV-2进入细胞需要直接结合SARS-COV-2 SPIKE（S） - 蛋白与主蛋白 宿主蛋白酶-TMPRSS2和血管紧张素转化酶2（ACE-2）受体，该酶在 多种主机单元类型。开发有效疫苗以防止SARS-COV-2的传播代表 一个巨大的进步，将有助于遏制Covid-19-19的大流行，但是令人关注的变体的出现 例如B1.1.7，P1和B1.351，可以逃避疫苗诱导的体液的中和反应 免疫反应强调了迫切需要开发新型疗法以完成疫苗接种工作。 根据我们的挑衅性支持数据，我们提出了SARS-COV-2的总体假设 诱导的肺内皮损伤是COVID-19引起的不良适应性炎症性损伤的必要元素 被治疗针对性。我们提出以下具体目标：在AIM 1中，我们将定义性质和基础 COVID-19诱导的ALI/ARDS的肺内皮损伤机理。我们将检验以下假设 肺内皮损伤程度是多个SARS- COV-2变体。我们将建立SARS-COV-2诱导的肺血管损伤和代偿性肺内皮 使用两个完整的人源化ACE2小鼠模型的再生，EC特异性遗传谱系追踪， VE-钙粘着蛋白和单细胞RNA测序的遗传稳定。在AIM 2中，我们将定义效率和最佳 两种有针对性的药物治疗策略的临时窗口，以防止和解决SARS-COV- 2诱导肺内皮损伤。我们将测试以下假设：设计的固体HACE-2胡椒有一个 比WildType HACE-2肽更高的治疗效率在减少肺内皮损伤方面以及长期 EC通过防止多个SARS-COV-2变体的病毒进入和传播来重新编程。我们将测试 推论假设，并使用改良的IL-1受体拮抗剂靶向抑制IL1β信号 防止多个SARS-COV2引起的前馈发炎环和内皮损伤 变体。我们将使用两种HACE-2鼠标模型，并比较不同的交付途径（气管内与 静脉内）并确定治疗干预的最佳临时窗口。