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

基本信息

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
项目类别：
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

项目摘要

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.

摘要/摘要虽然许多感染 SARS-CoV2 的人症状较轻，甚至可能无症状，但有些人患者经历的暴发性病理可能会导致严重的后遗症，甚至对其他人造成死亡。对感染的急性反应会持续数月（“长新冠病毒”）。加剧已有的疾病，特别是与代谢疾病相关的疾病。建议采取干预措施来限制长期的 COVID-19 严重程度：1) 感染是最成问题的患有高危代谢综合征的个体；2) 感染的严重程度与以下参数相关：与胰岛素抵抗有关，包括炎症、血糖水平升高伴严重胰岛素抵抗，高瘦素血症和糖尿病在肥胖人群中很常见，而且肝脏损伤增加。人们早就知道瘦素在调节免疫系统和新陈代谢方面发挥着重要作用。我们对肥胖/糖尿病与疾病加重之间的联系非常感兴趣在这里，我们的目标是直接检验减少的假设。血浆瘦素水平或增加的 MSH 水平对免疫系统和纤维化具有积极影响。我们将在细胞、组织和系统层面解决这些问题，具体来说，我们想要： 1：确定。 α-MSH 对瘦素-POMC 信号在介导免疫反应中的作用 COVID 2：确定瘦素中和是否对肺纤维化有影响。博来霉素纤维化模型3：确定瘦素中和是否对炎症有影响。 4：确定瘦素中和和降低瘦素的噻唑烷二酮类药物的影响。结合 Long-Covid，这些研究将测试瘦素中和、α-MSH 和 PPARα 的效果。 Scherer 和 Elmquist 都有代谢方面的记录。并与知名传染病专家 Jyothi Nagajyothi 合作，进一步由耶鲁大学的 Deep Dixit 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来评估这些干预措施的有效性，包括亚临床炎症增加、持续纤维化和胰岛素敏感性恶化我们的初步数据强烈支持瘦素参与的前提。瘦素中和抗体减少啮齿类动物 COVID-19 病毒载量的疾病进展模型降低了 85%，并有效地重建了肺中至少部分脂联素水平。表达脂联素，但当它们转化为纤维化时，通过减少瘦素而失去脂联素。使用中和抗瘦素抗体似乎可以保留脂肪母细胞功能。我们认为，这是在以下背景下最切实、最可立即转化的干预措施之一：长新冠病毒。