Leptin Reduction as a Potent Mitigative Strategy for the Treatment of PASC

瘦素减少是治疗 PASC 的有效缓解策略

• 批准号: 10554019
• 负责人: JOEL K. ELMQUIST
• 金额: $ 79.16万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554019
• 关键词: 2019-nCoV; Acute; Address; Adipocytes; Administrative Supplement; Age; Antibodies; Biological Response Modifiers; Brain; COVID-19; COVID-19 patient; COVID-19 severity; Cells; Cessation of life; Communicable Diseases; Communication; Complication; Data; Diabetes Mellitus; Disease; Disease Outcome; Disease Progression; Effectiveness of Interventions; Fibrosis; Glucose; Hand; Hypothalamic structure; Immune response; Immune system; Individual; Infection; Inflammation; Inflammatory; Insulin Resistance; Intervention; Laboratories; Leptin; Leptin resistance; Lipids; Lipoblast; Liver; Long COVID; Lung; Mediating; Mediator of activation protein; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Mus; Myofibroblast; Neurons; Obesity; Organ; Outcome; Pathology; Patients; Peripheral; Peroxisome Proliferator-Activated Receptors; Persons; Pharmacology; Plasma; Play; Populations at Risk; Post-Acute Sequelae of SARS-CoV-2 Infection; Publishing; Pulmonary Fibrosis; Reagent; Records; Regulation; Research; Risk; Risk Factors; Rodent; Role; SARS-CoV-2 exposure; SARS-CoV-2 infection; Severities; Severity of illness; Signal Transduction; Specialist; Symptoms; T-Lymphocyte; Testing; Thiazolidinediones; Tissues; Viral; Viral Load result; acute symptom; adipokines; adiponectin; alpha-Melanocyte stimulating hormone; clinical implementation; cytokine release syndrome; diabetic; diabetic patient; effectiveness evaluation; experience; high risk; improved; in vivo; indium-bleomycin; insulin sensitivity; insulin sensitizing drugs; interest; leptin receptor; liver injury; long-term sequelae; macrophage; neutralizing antibody; novel coronavirus; obese patients; obese person; parent grant; preservation; reconstitution; response; tool; treatment strategy

Summary/Abstract While many individuals infected with SARS-CoV2 have mild symptoms and may even be asymptomatic, some patients experience fulminant pathology that can cause severe sequelae or even death. For others, the effects of the acute response to the infection linger for many months (“Long-COVID”). The infection has the potential to exasperate pre-existing conditions, in particular those related to metabolic disease. Several lines of evidence suggest the potential for intervention to limit prolonged COVID-19 severity: 1) Infections are most problematic in individuals with high risk metabolic syndrome; 2) The severity of the infection is associated with parameters that are related to insulin resistance, including inflammation, elevated glucose levels with severe insulin resistance, and increased liver damage. Hyperleptinemia and diabetes are common among the obese population, and it has long been known that leptin plays an important role in regulating the immune system as well as metabolism. We have taken an intense interest in the connection of obesity/diabetes and enhanced disease severity/outcome over the past two years. Here, we aim to directly test the hypothesis that reducing plasma leptin levels or increasing MSH levels has a positive impact on the immune system and fibrosis. We will address these questions at the cellular, tissue and systemic level. Specifically, we want to: 1: Determine the role of -MSH towards leptin-POMC signaling in mediating immune responses in the context of Long- COVID centrally. 2: Determine whether leptin neutralization has an impact on lung fibrosis in the bleomycin fibrosis model. 3: Determine whether leptin neutralization has an impact on inflammation peripherally. 4: Determine the impact of leptin neutralization and leptin-lowering thiazolidinediones on Long-Covid. Combined, these studies will test the effect of leptin neutralization, -MSH and PPAR activation on disease outcome in long COVID. Both Scherer and Elmquist have track records in metabolism and have teamed up with Jyothi Nagajyothi, an established infectious disease specialist and are further supported by Deep Dixit at Yale and Jerry Colca from Cirius Inc. As a team between the three core laboratories, we believe we have unique expertise and tools in hand to assess the effectiveness of these interventions, including the increased subclinical inflammation, persistent fibrosis and deteriorated insulin sensitivity that persists during Long-COVID. Our preliminary data strongly support the premise of leptin involvement in the disease progression with leptin neutralizing antibodies reducing the viral load in a rodent COVID-19 model by 85% and effectively reconstituting at least partially adiponectin levels in the lung. Lipoblasts in the lung express adiponectin, but lose it as they convert to fibrosis generating myofibroblasts. Leptin reduction through the use of neutralizing anti-leptin antibodies seems to preserve lipoblast function. We believe this constitutes one of the most tangible and immediately translatable interventions in the context of Long-COVID.

总结/摘要 虽然许多感染SARS-CoV 2的人症状较轻，甚至可能没有症状，但有些人 患者会经历爆发性病理，可能导致严重后遗症甚至死亡。对其他人来说， 对感染的急性反应持续数月（“长期COVID”）。感染有可能 恶化先前存在的状况，特别是与代谢疾病有关的状况。若干条证据 这表明有可能采取干预措施来限制COVID-19的长期严重程度：1）感染在以下方面最成问题： 具有高风险代谢综合征的个体; 2）感染的严重程度与 与胰岛素抵抗有关，包括炎症，葡萄糖水平升高伴严重胰岛素抵抗， 并增加肝脏损伤。高瘦素血症和糖尿病在肥胖人群中很常见， 长期以来，人们都知道瘦素在调节免疫系统和新陈代谢方面起着重要作用。 我们对肥胖/糖尿病和增强疾病之间的联系非常感兴趣， 过去两年的严重程度/结果。在这里，我们的目标是直接测试假设，减少 血浆瘦素水平或升高的血清MSH水平对免疫系统和纤维化有积极影响。 我们将在细胞、组织和系统水平上解决这些问题。具体而言，我们要：1：确定 在长-短-长-短 COVID中心。2：确定瘦素中和是否对肺纤维化有影响， 博莱霉素纤维化模型。3：确定瘦素中和是否对炎症有影响 外围的4：确定瘦素中和和降低瘦素的噻唑烷二酮类药物对 长期新冠肺炎结合起来，这些研究将测试瘦素中和，β-MSH和PPAR γ的作用。 激活对长期COVID疾病结果的影响。谢勒和埃尔姆奎斯特在新陈代谢方面都有记录 并与著名传染病专家Jyothi Nagajyothi合作， 由耶鲁大学的Deep Diplomacy和Cirius Inc.的Jerry Colca提供支持。作为三个核心实验室之间的团队， 我们相信，我们拥有独特的专业知识和工具，可以评估这些干预措施的有效性， 包括增加的亚临床炎症、持续的纤维化和恶化的胰岛素敏感性， 在长期COVID期间持续存在。我们的初步数据强烈支持瘦素参与的前提， 瘦素中和抗体降低啮齿动物COVID-19病毒载量的疾病进展 通过85%的模型和有效地重建至少部分脂联素水平在肺中。肺中的成脂细胞 表达脂联素，但当它们转化为纤维化产生肌成纤维细胞时失去脂联素。瘦素减少通过 使用中和性抗瘦素抗体似乎保留了成脂细胞功能。 我们认为，这是最具体和立即可以翻译的干预措施之一， 长期新冠肺炎。