NF-kappaB and Mitochondrial Signals as Positive and Negative Regulators of Inflammation

NF-kappaB 和线粒体信号作为炎症的正向和负向调节剂

• 批准号: 10182897
• 负责人: Michael Karin
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-29 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10182897
• 关键词: 2019-nCoV; Administrative Supplement; Adult Respiratory Distress Syndrome; Age; Aging; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Antibodies; Antidiabetic Drugs; Attenuated; Award; Bacterial Infections; Blood Platelets; COVID-19; COVID-19 pandemic; Cause of Death; Cell Death; Cells; Complex; Coronavirus; Cytokeratin-18 Staining Method; Dendritic Cells; Epithelial Cells; Formalin; Funding; Goals; Guanidines; Half-Life; Healthcare Systems; Hepatocyte; High Fat Diet; Histology; Human; Immune; In Vitro; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Inhalation; Interleukin-1; Interleukin-1 alpha; Interleukin-1 beta; Interleukin-18; Interleukin-6; Lead; Left; Lung; Macrophage Activation; Mediating; Medical; Metformin; Mitochondria; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Parents; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenols; Prevention; Production; Property; RNA; Regulation; Research; Risk; Risk Factors; SARS coronavirus; Savings; Severe Acute Respiratory Syndrome; Severity of illness; Signal Transduction; TNF gene; Testing; The Jackson Laboratory; Therapeutic Intervention; Thinness; Tissues; Transgenic Mice; Viral Pneumonia; Virus; Virus Replication; age related; aged; anti aging; antimicrobial; base; biosafety level 3 facility; cell type; clinical development; cost; cytokine; exosome; experimental study; improved; in vivo; inhibitor/antagonist; mRNA Expression; macrophage; mortality; nanoparticle; neutrophil; novel; prevent; promoter; receptor; response; tissue injury

ABSTRACT This is a request for an Administrative Supplement to expand our current research on the regulation of NLRP3 inflammasome activation, carried out under parent award AI043477, with the goal of developing a novel anti- inflammatory therapy for COVID-19 related acute respiratory distress syndrome (ARDS). Like its predecessor, the Severe Acute Respiratory Syndrome-related coronavirus (SARS-CoV-1), the novel SARS-CoV-2 virus, the cause of the COVID-19 pandemic, can establish lower airway infections that cause viral pneumonia that may progress to ARDS. ARDS is a potentially fatal, severe medical condition that has been estimated to cause 200,000 yearly cases in the U.S., prior to the COVID-19 pandemic and many more now. Several innate immune cell types including platelets, neutrophils, macrophages and dendritic cells partake in mounting uncontrolled inflammation and tissue injury in ARDS, regardless of its initial trigger. These cells produce numerous inflammatory mediators and cytokines in response to the initial insult, which in the case of COVID-19 is viral replication within lung epithelial cells and subsequent cell death. Dying epithelial cells release damage associated molecular patterns (DAMPs), of which IL-1α and ATP are of primary importance. Together these molecules lead to priming (IL-1a) of alveolar macrophages and activation (ATP) of the NLRP3 inflammasome, which mediates production of mature IL-1β and IL-18, which amplify and propagate the inflammatory response that culminates in ARDS. Inhibition of this response should reduce much of the mortality and morbidity associated with COVID-19. However, since total IL-1 blockade with currently available drugs increases the risk of bacterial infections, the only suitable strategies for inhibition of SARS-CoV-2 elicited ARDS are either selective IL-1α blockade or inhibition of the NLRP3 inflammasome, which is not involved in anti-microbial defenses. So far, targeting of the downstream cytokine IL-6 had produced mixed results and IL-1a specific antibodies are still under clinical development. Moreover, anti-cytokine drugs are quite costly. We recently found the widely prescribed anti-diabetic drug metformin to be an effective inhibitor of NLRP3 inflammasome activation and IL-1β production by activated macrophages in vitro and in vivo. Accordingly, we now ask for additional funding to test and improve the ability of metformin to block the onset of ARDS, first in LPS-challenged Bl6 mice and then in SARS-CoV-2 infected hACE2-transgenic mice. As metformin has a short half-life and macrophages do not express the metformin transporters expressed by hepatocytes, we will examine whether metformin-loaded nanoparticles or exosomes given by inhalation allow for more effective inhibition of SARS-CoV-2 elicited ARDS. Importantly, metformin is a very safe and inexpensive drug with strong anti-aging properties that may be of further value in attenuating the well documented age-related increases in ARDS and COVID-19 risk, attributed to inflamma-aging.

摘要 这是一项行政补充请求，以扩大我们目前对NLRP监管的研究3 炎性小体激活，在母公司奖AI043477下进行，目的是开发一种新的抗- COVID-19相关急性呼吸窘迫综合征（ARDS）的炎症治疗。与其前身一样， 严重急性呼吸综合征相关冠状病毒（SARS-CoV-1）、新型SARS-CoV-2 引起COVID-19大流行的病毒，可以建立引起病毒性肺炎的下呼吸道感染 可能发展为ARDS。ARDS是一种潜在致命的严重医学疾病，据估计， 在美国每年造成20万例，在COVID-19大流行之前，现在更多。几个先天的 包括血小板、嗜中性粒细胞、巨噬细胞和树突细胞在内的免疫细胞类型参与安装 不受控制的炎症和组织损伤，无论其最初的触发。这些细胞产生 许多炎症介质和细胞因子对初始损伤的反应，在COVID-19的情况下， 是肺上皮细胞内的病毒复制和随后的细胞死亡。死亡的上皮细胞释放损伤 相关分子模式（DAMP），其中IL-1 α和ATP是最重要的。综合这些 分子导致肺泡巨噬细胞的引发（IL-1a）和NLRP 3炎性体的活化（ATP）， 其介导成熟IL-1 β和IL-18的产生，其放大和传播炎症反应 最终导致ARDS抑制这一反应应可降低大部分相关的死亡率和发病率 新冠肺炎然而，由于目前可用的药物完全阻断IL-1会增加细菌感染的风险， 感染，抑制SARS-CoV-2引起的ARDS的唯一合适的策略是选择性IL-1 α 阻断或抑制NLRP 3炎性体，其不参与抗微生物防御。到目前为止， 靶向下游细胞因子IL-6产生了混合的结果，IL-1a特异性抗体仍然是 在临床开发中。此外，抗细胞因子药物相当昂贵。我们最近发现， 处方抗糖尿病药物二甲双胍是NLRP3炎性小体激活和IL-1 β的有效抑制剂 在体外和体内由活化的巨噬细胞产生。因此，我们现在要求增加资金， 并提高二甲双胍阻断ARDS发作的能力，首先是在LPS激发的B16小鼠中，然后是在 SARS-CoV-2感染hACE2转基因小鼠。由于二甲双胍的半衰期短，而巨噬细胞没有 表达肝细胞表达的二甲双胍转运蛋白，我们将检查二甲双胍负载的 通过吸入给予的纳米颗粒或外来体允许更有效地抑制SARS-CoV-2引起的ARDS。 重要的是，二甲双胍是一种非常安全和廉价的药物，具有很强的抗衰老特性， 进一步的价值在于减轻有充分证据证明的与年龄相关的ARDS和COVID-19风险增加， 炎症老化