Investigating the link between pericyte dysfunction and loss of glucose homeostasis in COVID-19
研究 COVID-19 中周细胞功能障碍与葡萄糖稳态丧失之间的联系
基本信息
- 批准号:10662533
- 负责人:
- 金额:$ 38.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVACE2AffectAmino Acid SequenceAngiotensin IIAnimal ModelAutopsyBlood GlucoseBlood VesselsBlood flowCOVID-19COVID-19 patientCellsCoronavirusDataDiabetes MellitusEndocrineEndocytosisFunctional disorderGlucose IntoleranceHamstersHealthHealthcareHormone secretionHumanHypoxiaImmunohistochemistryImpairmentIncubatedInfectionInfiltrationInflammationInjectionsIslets of LangerhansLesionLinkLungMicrovascular DysfunctionModelingOrganPancreasPancreatic DiseasesPancreatitisPatientsPatternPericytesPersonsPhenotypePredispositionPropertyProteinsPublishingRecombinant ProteinsRecombinantsResearchRespiratory FailureSARS-CoV-2 infectionSARS-CoV-2 spike proteinSliceSpecimenSurfaceTestingTimeTissuesTropismVascular SystemVascularizationVasodilator AgentsViralVirusVirus DiseasesVirus Receptorsangiotensin I (1-7)blood glucose regulationcellular targetingdiabetes pathogenesisdisease natural historyfunctional disabilityglobal healthglucose metabolismhistopathological examinationin vivoisletmortalitynon-diabeticnovelnovel coronavirusparticlepermissivenessreceptorresponsesmall molecule inhibitorspatiotemporalvasoconstrictionvasomotion
项目摘要
ABSTRACT
The coronavirus disease 2019 (COVID-19) is a global healthcare crisis that in the USA kills about 1 person every
minute. It is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). While respiratory
failure is still the most common cause of mortality in COVID-19 patients, serious manifestations are seen across
multiple organs, including the pancreas. There is an intricate relationship between COVID-19 and pancreatic
diseases such as pancreatitis and diabetes. Understanding the pathophysiological mechanisms that lead to
pancreatic dysfunction and glucose intolerance in infected patients is of utmost importance. The pathogenesis
of diabetes is intimately associated with the dysfunction of the pancreatic islet. There are numerous studies
indicating that SARS-CoV-2 directly attacks the vascular system. However, the possibility that islet microvascular
dysfunction triggers loss of glucose homeostasis in COVID-19 patients has not been explored. This project
focuses on the vascular pericyte because our published and preliminary data show that (a) pericytes in human
islets are very responsive to angiotensin II and express the key host cellular receptor of SARS-CoV-2, ACE2;
(b) pericytes can be infected with SARS-CoV-2 pseudo-entry viruses; and (c) incubation with a SARS-CoV-2
Spike recombinant protein increases pericyte basal Ca2+ levels. We therefore hypothesize that SARS-CoV-2
infects pancreas pericytes, interfering with their contractile properties and impairing their function. Pericyte
dysfunction will decrease local blood flow, leading to tissue hypoxia and inflammation and compromising
endocrine cell activity. We will test this hypothesis using living pancreas slices from humans and hamsters which
are a suitable animal model for COVID-19 research given the high homology of their ACE2 protein sequences.
This hypothesis will be tested in two Aims: 1) determine if pericytes are cellular targets of SARS-CoV-2 in the
pancreas, and (2) examine the effects of SARS-CoV-2 on islet pericyte function and microvascular responses
ex vivo and in vivo. In Aim 1, we will search for SARS-CoV-2 viral particles, characterize microvascular lesions
and the pericyte phenotype in the pancreas of COVID-19 patients. We will infect living pancreas slices with
SARS-CoV-2 pseudo-entry and live viruses and determine if pericytes are permissive for infection. In Aim 2, we
will assess the functional consequences of manipulating ACE2 expression and activity through interactions with
SARS-CoV-2 spike protein on pericyte Ca2+ responses and vasomotion ex vivo in living pancreas slices, and in
vivo by intraductal injections of pseudo-entry viruses in the hamster pancreas. We will follow longitudinally the
effects on glucose metabolism, as well as changes in local hypoxia, inflammation, endocrine cell mass and
function. This research has the potential to identify a mechanism of dysfunction in the endocrine pancreas. If the
hypothesis is correct, pericytes are cellular targets of this coronavirus. Their functional impairment could explain
why COVID-19 is linked to a loss of glucose homeostasis and other pancreatic disorders. We anticipate our
study of COVID-19–related diabetes to uncover novel mechanisms of the natural history of this disease.
摘要
2019年冠状病毒病(COVID-19)是一场全球性的医疗危机,在美国,每年约有1人死亡。
一下它是由严重急性呼吸道综合征冠状病毒-2(SARS-CoV-2)引起的。当呼吸
失败仍然是COVID-19患者死亡的最常见原因,
多个器官包括胰腺COVID-19和胰腺癌之间存在着错综复杂的关系,
胰腺炎和糖尿病等疾病。了解导致
感染患者的胰腺功能障碍和葡萄糖耐受不良是最重要的。发病机制
糖尿病的发病与胰岛功能障碍密切相关。有许多研究
表明SARS-CoV-2直接攻击血管系统。然而,胰岛微血管
在COVID-19患者中,功能障碍引发葡萄糖稳态丧失的研究尚未进行。这个项目
因为我们发表的和初步的数据表明,(a)人的周细胞
胰岛对血管紧张素II非常敏感,并表达SARS-CoV-2的关键宿主细胞受体ACE 2;
(b)周细胞可以被SARS-CoV-2假侵入病毒感染;和(c)与SARS-CoV-2
刺突重组蛋白增加周细胞基础Ca 2+水平。因此,我们假设SARS-CoV-2
感染胰腺周细胞,干扰其收缩特性并损害其功能。周细胞
功能障碍将减少局部血流量,导致组织缺氧和炎症,并损害
内分泌细胞活性我们将使用人类和仓鼠的活胰腺切片来检验这一假设,
是COVID-19研究的合适动物模型,因为它们的ACE 2蛋白序列高度同源。
这一假设将在两个目标中进行测试:1)确定周细胞是否是SARS-CoV-2在细胞中的靶细胞。
胰腺,以及(2)检测SARS-CoV-2对胰岛周细胞功能和微血管反应的影响
离体和体内。在目标1中,我们将寻找SARS-CoV-2病毒颗粒,表征微血管病变
以及COVID-19患者胰腺中的周细胞表型。我们将感染活的胰腺切片
SARS-CoV-2假进入和活病毒,并确定周细胞是否允许感染。在目标2中,
将评估通过与以下物质的相互作用操纵ACE 2表达和活性的功能后果:
SARS-CoV-2刺突蛋白对离体活胰腺切片中周细胞Ca 2+反应和血管舒缩的影响,以及
通过在仓鼠胰腺中导管内注射假进入病毒体内。我们将纵向跟踪
对葡萄糖代谢的影响,以及局部缺氧、炎症、内分泌细胞质量和
功能这项研究有可能确定内分泌胰腺功能障碍的机制。如果
假设是正确的,周细胞是这种冠状病毒的细胞靶点。他们的功能障碍可以解释
为什么COVID-19与葡萄糖稳态丧失和其他胰腺疾病有关。我们期待我们的
COVID-19相关糖尿病的研究,以揭示这种疾病自然史的新机制。
项目成果
期刊论文数量(0)
专著数量(0)
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Joana Almaca其他文献
Joana Almaca的其他文献
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{{ truncateString('Joana Almaca', 18)}}的其他基金
Integrative analysis of multi-omic signatures and cellular function in human pancreas across developmental timeline at single-cell spatial resolution
以单细胞空间分辨率对人类胰腺跨发育时间线的多组学特征和细胞功能进行综合分析
- 批准号:
10584251 - 财政年份:2022
- 资助金额:
$ 38.38万 - 项目类别:
Role of pericytes in pancreatic islet fibrosis
周细胞在胰岛纤维化中的作用
- 批准号:
10374421 - 财政年份:2017
- 资助金额:
$ 38.38万 - 项目类别:
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