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.

抽象的 这是向行政补充的请求，以扩大我们目前对NLRP3法规的研究 根据父母奖AI043477进行的炎症激活，目的是开发一种新颖的抗 COVID-19相关急性呼吸窘迫综合征（ARDS）的炎症疗法。像它的前任一样 新型SARS-COV-2 病毒是COVID-19大流行的原因，可以建立引起病毒性肺炎的下气道感染 这可能会发展为ards。 ARDS是一种潜在的致命严重医疗状况，据估计 在美国19日大流行之前，在美国造成200,000年的案件。几个先天 免疫细胞类型，包括血小板，中性粒细胞，巨噬细胞和树突状细胞包括在安装中 不受控制的注射和组织损伤，无论其初始触发因素如何。这些细胞产生 响应初始侮辱的许多炎症介质和细胞因子，在Covid-19 是肺上皮细胞内的病毒复制和随后的细胞死亡。垂死的上皮细胞释放损害 相关的分子模式（潮湿），其中IL-1α和ATP至关重要。在一起 分子导致肺泡巨噬细胞的启动（IL-1A）和NLRP3炎性体的激活（ATP）， 它介导成熟的IL-1β和IL-18的产生，从而扩大和传播炎症反应 这最终达到了ARDS。抑制这种反应应降低相关的大部分死亡率和发病率 与Covid-19。但是，由于目前可用药物的总IL-1阻滞增加了细菌的风险 感染，抑制SARS-COV-2的唯一合适策略是选择性IL-1α NLRP3炎性体的阻断或抑制，这与抗微生物防御无关。迄今为止， 下游细胞因子IL-6的靶向产生了混合的结果，IL-1A特异性抗体仍然是 在临床发展下。此外，抗周围药物的成本很高。我们最近发现了广泛的 规定的抗糖尿病药物二甲双胍是NLRP3炎性体激活和IL-1β的有效抑制剂 通过活化的巨噬细胞在体外和体内产生。彼此之间，我们现在要求额外的资金进行测试 并提高二甲双胍阻断ARDS发作的能力，首先是在LPS挑战的BL6小鼠中，然后在 SARS-COV-2感染HACE2-转基因小鼠。因为二甲双胍的半衰期很短，巨噬细胞没有 表达用肝细胞表达的二甲双胍转运蛋白，我们将检查是否负载二甲双胍 吸入给出的纳米颗粒或外泌体可以更有效地抑制SARS-COV-2引起的ARDS。 重要的是，二甲双胍是一种非常安全且廉价的药物，具有强大的抗衰老特性 降低了与年龄相关的ARDS和COVID-19风险增加的进一步价值，归因于 炎症。