COVID-19: HDL's Role in Innate Immunity and Cardiovascular Protection with COVID-19
COVID-19:HDL 在 COVID-19 的先天免疫和心血管保护中的作用
基本信息
- 批准号:10404924
- 负责人:
- 金额:--
- 依托单位:
- 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 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAcute Respiratory Distress SyndromeAcute-Phase ReactionAgeAnti-Bacterial AgentsAnti-Inflammatory AgentsApolipoprotein A-IApolipoprotein EAtherosclerosisBacterial InfectionsBasic ScienceBiological AssayBiologyCOVID-19COVID-19 assayCOVID-19 impactCOVID-19 mortalityCOVID-19 patientCardiovascular DiseasesCardiovascular systemCause of DeathCessation of lifeCholesterolClinicalClinical TrialsCollaborationsCoronavirusDangerousnessDataDevelopmentDiabetes MellitusDiseaseEpithelial CellsFunctional disorderGoalsHIVHIV InfectionsHeart DiseasesHepaticHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHypertriglyceridemiaImmunologyImpairmentInfectionInflammationInflammatoryInflammatory ResponseInfluenzaInnate Immune SystemInterferon-betaIntrinsic factorKnowledgeLeadLipidsLipoproteinsLungMediatingMembrane FusionMetabolicMorbidity - disease rateNatural ImmunityNon-Insulin-Dependent Diabetes MellitusObesityOutcomePathway interactionsPatientsPeptidesPersonsPlayProductionPropertyProteinsProteomicsRecombinantsRiskRoleRunningSARS-CoV-2 infectionSamplingScaffolding ProteinSepsisSymptomsTestingTherapeuticTroponinUnited StatesVeteransViralVirus DiseasesVirus Replicationcoronavirus diseasecytokinehigh riskimprovedinnovationlipidomicsmacrophagemortalitynovel coronavirusparticlepeptidomimeticsprotein expressionproteomic signatureresponsesevere COVID-19symptomatic COVID-19systemic inflammatory responsetargeted treatmenttranslational therapeutics
项目摘要
COVID19: HDL’s Role in Innate Immunity and Cardiovascular Protection with COVID-19
The novel coronavirus (SARS-CoV-2) causes a disease called COVID-19. For many people, COVID-19 has
almost no symptoms, yet for others, COVID-19 is particularly dangerous and has high morbidity and mortality
rates. People with pre-existing type-2 diabetes and atherosclerotic cardiovascular disease (ASCVD) have twice
the risk of SARS-CoV-2 infection and are more likely to have poor outcomes. 70% of patients with ASCVD and
elevated troponin die of COVID. We don’t know what intrinsic factors contribute to these disparate outcomes.
High Density Lipoprotein (HDL) particles play a critical role in the innate immune system and are protective
against viral and bacterial infections. HDL particles best are known for their roles protecting from atherosclerotic
cardiovascular disease (ASCVD). The cardiovascular protection conferred by HDL is largely mediated by HDL’s
associated proteins, which comprise about half of HDL’s mass. Mechanisms for HDL’s protection from ASCVD
are shared with mechanisms for HDL’s protection from viral infections. These protective properties center around
the HDL-associated proteins that mediate its anti-inflammatory and antioxidative functions. The goal of this
project is to define how HDL may protect from Sars-CoV-2 infection and limit the inflammatory response to
COVID-19 illness. Obesity and type-2 diabetes (DM2) lead to hypertriglyceridemia and metabolic changes that
impair HDL’s anti-inflammatory and antioxidative functions. We will define if DM2 leads to HDL dysfunction and
contributes to severe COVID-19 outcomes.
Our overarching hypothesis is that HDL’s antiviral properties can limit SARS-CoV-2 infection and that HDL’s
anti-inflammatory and antioxidative capacity limit the systemic inflammatory response to COVID-19. We have
initiated a collaboration with Dr. Malall, an immunology expert running a large trial with COVID-19 patients whose
de-identified samples are paired with de-identified EMR outcomes data. In AIM1 we will test the hypothesis that
SARS-CoV-2 infection impairs HDL’s antioxidative and anti-inflammatory capacities, and that these changes can
be predicted by proteomic signatures of HDL. We also have collaboration with Dr. Denison, an expert in
coronavirus biology. In AIM2 we will test the hypothesis that HDL can reduce SARS-CoV-2 infectivity of lung
epithelial cells, but that COVID-19 impairs HDL’s antiviral capacity, which can be improved with Remdesavir
treatment. In AIM3 we will test the hypothesis that type-2 diabetes alters the HDL-associated protein networks
that limit systemic inflammation with COVID-19 and protect against SARS-CoV-2 infection.
Diabetes and cardiovascular disease are among the most prevalent problems among United States
Veterans, making Veterans more likely to have poor COVID-19 outcomes. An asset to this project is that we can
relate our HDL function and antiviral assays with clinical outcomes. Our studies will define proteomic signatures
from HDL that are important for its antiviral effects. We ultimately aim to use HDL-directed therapies like
recombinant Apo-A1 peptides to improve COVID outcomes.
COVID-19:HDL在先天免疫和COVID-19心血管保护中的作用
新型冠状病毒(SARS-CoV-2)引起一种称为COVID-19的疾病。对许多人来说,COVID-19
几乎没有症状,但对其他人来说,COVID-19特别危险,发病率和死亡率很高
rates.患有2型糖尿病和动脉粥样硬化性心血管疾病(ASCVD)的人有两次
SARS-CoV-2感染的风险,并且更可能有不良结果。70%的ASCVD患者,
肌钙蛋白升高死于新冠肺炎我们不知道是什么内在因素导致了这些不同的结果。
高密度脂蛋白(HDL)颗粒在先天免疫系统中起着关键作用,
防止病毒和细菌感染。高密度脂蛋白颗粒最为人所知的作用是防止动脉粥样硬化
心血管疾病(ASCVD)。高密度脂蛋白对心血管的保护作用主要由高密度脂蛋白介导,
相关蛋白质,约占HDL质量的一半。HDL保护ASCVD的机制
与HDL保护免受病毒感染的机制相同。这些保护特性围绕着
介导其抗炎和抗氧化功能的HDL相关蛋白。这个目标
该项目的目的是确定HDL如何保护免受SARS-CoV-2感染,并限制炎症反应,
COVID-19疾病。肥胖和2型糖尿病(DM 2)导致高脂血症和代谢变化,
损害HDL抗炎和抗氧化功能。我们将确定DM 2是否导致HDL功能障碍,
导致严重的COVID-19后果。
我们的首要假设是HDL的抗病毒特性可以限制SARS-CoV-2感染,
抗炎和抗氧化能力限制了对COVID-19的全身炎症反应。我们有
发起了与马拉尔博士的合作,马拉尔博士是一位免疫学专家,他对COVID-19患者进行了一项大型试验,
去识别样本与去识别EMR结果数据配对。在AIM 1中,我们将测试假设,
SARS-CoV-2感染损害HDL的抗氧化和抗炎能力,这些变化可以
可以通过HDL的蛋白质组学特征来预测。我们还与丹尼森博士合作,丹尼森博士是
冠状病毒生物学在AIM 2中,我们将检验HDL可以降低SARS-CoV-2肺感染性的假设
上皮细胞,但COVID-19损害HDL的抗病毒能力,这可以通过Remdesavir改善
治疗在AIM 3中,我们将检验2型糖尿病改变HDL相关蛋白网络的假设
这限制了COVID-19引起的全身性炎症,并防止了SARS-CoV-2感染。
糖尿病和心血管疾病是美国最普遍的问题之一
退伍军人,使退伍军人更有可能有不良的COVID-19结果。这个项目的一个优点是我们可以
将我们的HDL功能和抗病毒检测与临床结果联系起来。我们的研究将定义蛋白质组特征
对它的抗病毒作用很重要。我们最终的目标是使用HDL导向疗法,
重组Apo-A1肽改善COVID预后。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John Michael Stafford其他文献
John Michael Stafford的其他文献
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{{ truncateString('John Michael Stafford', 18)}}的其他基金
COVID-19: HDL's Role in Innate Immunity and Cardiovascular Protection with COVID-19
COVID-19:HDL 在 COVID-19 的先天免疫和心血管保护中的作用
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10153344 - 财政年份:2021
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CETP and Sex-Differences in Metabolic and Cardiovascular Disease
CETP 与代谢和心血管疾病的性别差异
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10407032 - 财政年份:2019
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Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk
雌激素调节代谢和心血管风险的治疗潜力
- 批准号:
10184832 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Estrogen and coordinated carbohydrate and lipid metabolism in obesity
肥胖中的雌激素与碳水化合物和脂质代谢的协调
- 批准号:
9222748 - 财政年份:2016
- 资助金额:
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Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk
雌激素调节代谢和心血管风险的治疗潜力
- 批准号:
10899800 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk
雌激素调节代谢和心血管风险的治疗潜力
- 批准号:
10392424 - 财政年份:2016
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Therapeutic Potential of Estrogen-Regulated Metabolism and Cardiovascular Risk
雌激素调节代谢和心血管风险的治疗潜力
- 批准号:
10618133 - 财政年份:2016
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Cholesteryl ester transfer protein, a novel mediator of insulin sensitivity
胆固醇酯转移蛋白,一种新型胰岛素敏感性介质
- 批准号:
8966663 - 财政年份:2013
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Cholesteryl ester transfer protein, a novel mediator of insulin sensitivity
胆固醇酯转移蛋白,一种新型胰岛素敏感性介质
- 批准号:
8633281 - 财政年份:2013
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