Impact of obesity on SARS-CoV-2 infection and reciprocal effects of SARS-CoV-2 on metabolic disease

肥胖对 SARS-COV-2 感染的影响以及 SARS-COV-2 对代谢疾病的相互影响

基本信息

  • 批准号:
    10583175
  • 负责人:
  • 金额:
    $ 99.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-01 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

The COVID-19 global pandemic caused by the novel SARS-CoV-2 coronavirus continues to result in significant morbidity and mortality worldwide. Although effective vaccines and therapeutics have been introduced, COVID-19 will continue to persist as a public health issue as a result of vaccine resistance/hesitancy and risk of reinfection, the emergence of variants of concern that may evade current vaccines, and the potential existence of latent viral reservoirs. The adverse outcomes associated with COVID- 19 are increased by a number of pre-existing conditions, notably diabetes, cardiovascular disease, and hypertension. These conditions share obesity and insulin resistance (IR) as a common underlying feature, which has raised the question of whether obesity per se is an independent risk factor for more severe COVID- 19 outcomes in the absence of clinically diagnosed diabetes, cardiovascular disease, or hypertension. This concept is supported by previously described effects of obesity on respiratory disease and the immune response. Evidence is also accumulating for altered glucose and lipid metabolism and new-onset diabetes in COVID-19 patients that can persist after recovery from acute infection, and that constitutes an important component of post-acute sequelae of COVID-19 (PASC). These data suggest that, while obesity and metabolic disease affect the acute COVID-19, that there are a reciprocal acute and post-acute effects of COVID-19 on metabolic control. We hypothesize that: (1) obesity/IR in the absence of other conditions such as frank diabetes, CVD, or hypertension will increase the severity of SARS-CoV-2 infection and acute disease pathology; and (2) that SARS-CoV-2 infection will exacerbate pre-existing preclinical metabolic disease as reflected in progression to more advanced, clinically evident disease. We propose to address these hypotheses through pursuit of the following specific aims. Specific Aim 1. Determine the effect of pre-existing obesity/IR on the acute response to SARS-CoV-2 infection. Specific Aim 2. Determine the effect of SARS-CoV-2 infection on the post-acute progression of metabolic disease. We will employ a nonhuman primate preclinical model of lean, metabolically healthy and obese, insulin- resistant adult male rhesus macaques infected with SARS-CoV-2 over a 2-week (acute phase) or 6-month (post-acute) course of disease, during which time comprehensive longitudinal assessments of viral load, lung pathology, peripheral and adipose immune cell responses, and glucose and lipid metabolism will be performed. At necropsy following the acute and post-acute studies, islet function will be assessed and multiple tissue samples collected for determination of viral distribution and persistence in potential latent reservoirs. The proposed studies represent a unique opportunity to elucidate the mechanisms underlying the reciprocal relationship between COVID-19 and metabolic disease in an experimentally tractable preclinical model.
由新型 SARS-CoV-2 冠状病毒引起的 COVID-19 全球大流行继续导致 全球发病率和死亡率显着。尽管已经有了有效的疫苗和治疗方法 据介绍,由于疫苗的出现,COVID-19 将继续作为一个公共卫生问题持续存在 抵抗/犹豫和再次感染的风险,可能逃避当前病毒的关注变体的出现 疫苗,以及潜在病毒库的潜在存在。与新冠病毒相关的不良后果 19 因一些原有疾病而增加,特别是糖尿病、心血管疾病和 高血压。这些疾病都有肥胖和胰岛素抵抗 (IR) 作为共同的基本特征, 这就提出了一个问题:肥胖本身是否是更严重的新冠肺炎的独立危险因素? 19 在没有临床诊断糖尿病、心血管疾病或高血压的情况下的结果。这 先前描述的肥胖对呼吸系统疾病和免疫系统的影响支持了这一概念 回复。越来越多的证据表明,葡萄糖和脂质代谢的改变以及新发糖尿病的发生 COVID-19 患者在急性感染恢复后仍能持续存在,这构成了重要的 COVID-19 (PASC) 急性后遗症的组成部分。这些数据表明,虽然肥胖和代谢 疾病会影响急性 COVID-19,因此 COVID-19 对人体有相互的急性和急性后影响 代谢控制。我们假设:(1)在没有其他条件(例如坦率)的情况下肥胖/IR 糖尿病、CVD 或高血压会增加 SARS-CoV-2 感染和急性疾病的严重程度 病理; (2) SARS-CoV-2 感染会加剧已有的临床前代谢性疾病,因为 反映在进展为更晚期、临床上明显的疾病。我们建议解决这些问题 通过追求以下具体目标来提出假设。 具体目标 1. 确定先前存在的肥胖/IR 对 SARS-CoV-2 感染的急性反应的影响。 具体目标 2. 确定 SARS-CoV-2 感染对代谢急性进展的影响 疾病。 我们将采用非人类灵长类动物临床前模型,该模型具有瘦、代谢健康和肥胖、胰岛素- 感染 SARS-CoV-2 超过 2 周(急性期)或 6 个月的耐药成年雄性恒河猴 (急性后)病程,在此期间对病毒载量、肺脏进行全面纵向评估 将进行病理学、外周和脂肪免疫细胞反应以及葡萄糖和脂质代谢。 在急性和急性后研究后的尸检中,将评估胰岛功能并评估多个组织 收集样本用于确定潜在潜伏病毒库中的病毒分布和持久性。这 拟议的研究提供了一个独特的机会来阐明相互关系背后的机制 在实验上易于处理的临床前模型中,研究了 COVID-19 与代谢疾病之间的关系。

项目成果

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Paul Kievit其他文献

Paul Kievit的其他文献

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{{ truncateString('Paul Kievit', 18)}}的其他基金

Post-acute metabolic sequelae of SARS-CoV-2 infection in nonhuman primates
非人灵长类动物感染 SARS-CoV-2 后急性代谢后遗症
  • 批准号:
    10554898
  • 财政年份:
    2022
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of estrogen replacement on postmenopausal ART-associated comorbidity and viral latency
雌激素替代对绝经后 ART 相关合并症和病毒潜伏期的影响
  • 批准号:
    10326734
  • 财政年份:
    2021
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of estrogen replacement on postmenopausal ART-associated comorbidity and viral latency
雌激素替代对绝经后 ART 相关合并症和病毒潜伏期的影响
  • 批准号:
    10468267
  • 财政年份:
    2021
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of estrogen replacement on postmenopausal ART-associated comorbidity and viral latency
雌激素替代对绝经后 ART 相关合并症和病毒潜伏期的影响
  • 批准号:
    10624286
  • 财政年份:
    2021
  • 资助金额:
    $ 99.42万
  • 项目类别:
The impact of gastric bypass on maternal and offspring metabolic health
胃绕道手术对母婴代谢健康的影响
  • 批准号:
    10355478
  • 财政年份:
    2020
  • 资助金额:
    $ 99.42万
  • 项目类别:
The impact of gastric bypass on maternal and offspring metabolic health
胃绕道手术对母婴代谢健康的影响
  • 批准号:
    10557865
  • 财政年份:
    2020
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of obesity on HIV pathogenesis, antiretroviral therapy, and metabolic comorbidities
肥胖对 HIV 发病机制、抗逆转录病毒治疗和代谢合并症的影响
  • 批准号:
    10248477
  • 财政年份:
    2019
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of obesity on HIV pathogenesis, antiretroviral therapy, and metabolic comorbidities
肥胖对 HIV 发病机制、抗逆转录病毒治疗和代谢合并症的影响
  • 批准号:
    10438873
  • 财政年份:
    2019
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of obesity on HIV pathogenesis, antiretroviral therapy, and metabolic comorbidities
肥胖对 HIV 发病机制、抗逆转录病毒治疗和代谢合并症的影响
  • 批准号:
    10015274
  • 财政年份:
    2019
  • 资助金额:
    $ 99.42万
  • 项目类别:
Effect of obesity on HIV pathogenesis, antiretroviral therapy, and metabolic comorbidities
肥胖对 HIV 发病机制、抗逆转录病毒治疗和代谢合并症的影响
  • 批准号:
    10852482
  • 财政年份:
    2019
  • 资助金额:
    $ 99.42万
  • 项目类别:

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Mechanism of the short- and long-term effects of COVID-19-induced Alarmins on hematopoietic stem and progenitor cells.
COVID-19诱导的警报素对造血干细胞和祖细胞的短期和长期影响的机制。
  • 批准号:
    10836902
  • 财政年份:
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Investigating the role and therapeutic potential of the alpha5beta1 integrin in risk factors for COVID-19-associated cognitive impairment
研究 α5β1 整合素在 COVID-19 相关认知障碍危险因素中的作用和治疗潜力
  • 批准号:
    10658178
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  • 资助金额:
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Procoagulant platelets as biomarkers for post-COVID-19 cognitive decline
促凝血小板作为 COVID-19 后认知能力下降的生物标志物
  • 批准号:
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Mechanisms of SARS-CoV-2 pathogenesis during HIV/SIV infection
HIV/SIV 感染期间 SARS-CoV-2 的发病机制
  • 批准号:
    10685195
  • 财政年份:
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  • 资助金额:
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Optimizing the Generation of Monoclonal Antibodies for Prevention and Treatment of HSV Disease
优化用于预防和治疗 HSV 疾病的单克隆抗体的生成
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