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Beta cell dysfunction as an acute and a post acute sequelae of COVID19

β 细胞功能障碍是 COVID19 的急性和急性后遗症

基本信息

批准号：
10674887
负责人：
Senta K Georgia
金额：
$ 53.93万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
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：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674887
关键词：
2019-nCoV Accident and Emergency department Acute Address Adult Affect Animal Model Animals Atrophic Autopsy Beta Cell Biological Assay Biological Models COVID-19 COVID-19 impact COVID-19 pandemic COVID-19 pathogenesis COVID-19 patient COVID-19 survivors Cadaver Cell Respiration Cell Survival Cell physiology Cellular Metabolic Process Cessation of life Clinical DNA DNA Methylation Data Development Diabetes Mellitus Diabetic Ketoacidosis Disease Face Functional disorder Future Glucose Goals Health Human Hyperglycemia In Vitro Infection Injury Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Kidney Literature Long COVID Long-Term Effects Macaca mulatta Measures Mediating Metabolic Metabolism Mitochondria Modeling Molecular Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Odds Ratio Outcome Pancreas Paper Pathogenesis Pathology Patients Physiological Plasma Post-Acute Sequelae of SARS-CoV-2 Infection Predisposition Prevalence Primates Registries Reporting Reproducibility Resolution Respiratory System SARS-CoV-2 infection SARS-CoV-2 pathogenesis Sampling Secondary to Serum Stress Structure of beta Cell of islet Study models Symptoms Techniques Testing Therapeutic Intervention Transplantation Viral Pathogenesis acute infection blood glucose regulation capsule cell free DNA cell injury clinical phenotype clinically relevant design diabetes pathogenesis experimental study improved in vivo in vivo Model innovation insight insulin dependent diabetes mellitus onset insulin secretion islet long term consequences of COVID-19 long term recovery methylation pattern nonhuman primate observational cohort study post-transplant prevent programs severe COVID-19 small molecule

项目摘要

PROJECT SUMMARY Beta cell dysfunction and death are significant pathologies underlying the development of Type 2 diabetes. Our long-term goal is to identify molecular mechanisms restrict beta cell function and survival. During the SARS- CoV2-driven COVID19 pandemic, there are reports of adult COVID19+ patients presenting with diabetic ketoacidosis in emergency rooms. 25% of new-onset type 1 diabetes (T1D) patients presenting with diabetic ketoacidosis in the T1D Exchange registry are COVID19+. Our group has reported a significant increase in the number of new-onset type 2 diabetes patients presenting in diabetic ketoacidosis. This suggests that the pathogenesis of COVID19 may have acute and specific effects on pancreatic beta cell function. One of the barriers to understanding how SARS-CoV2 infection may affect beta cell function and survival in patients is the limited number of physiologically relevant animal models to study. We have capitalized on unique access the pancreas of SCV2-innoculated animals to model and understand how the infection may affect beta cell function and survival. Our preliminary data that shows: (1) SARS-CoV2 directly infects beta cells, (2) SARS-CoV2 infection causes dramatic morphological changes in islet, (3) SARS-CoV2 infection shifts beta cell metabolism to glycolytic profile, and (4) SARS-CoV2 infection results in decreased in beta cell function and survival. The objective of this proposal is to define the mechanisms that drive the post-acute consequences of COVID19-mediated beta cell injury in vivo. There is controversy in the literature regarding if SARS-CoV2 directly infects beta cells and affects beta cell function and survival or if the disruption of glucose homeostasis in patients is secondary. We hypothesize that SARS-CoV2 infection reprograms cellular metabolism and induces necroptosis, thus leaving hosts susceptible to beta cell dysfunction acutely and as a post-acute sequelae of COVID19. These highly innovative experiments capitalize on a unique and clinically relevant model system and employs cutting edge techniques to assess how beta cell survival and metabolism are affected by SARS-CoV2 infection. These experiments will provide critical mechanistic insight to the underpinnings of the emerging clinical phenotype of acute hyperglycemia, diabetic ketoacidosis, and potentially lifelong diabetes that may afflict a significant number of patients who have recovered from COVID19.

项目总结 β细胞功能障碍和死亡是2型糖尿病发生的重要病理基础。我们的长期目标是确定限制β细胞功能和存活的分子机制。在SARS期间- CoV2驱动的COVID19大流行，有报道称成年COVID19+患者出现糖尿病急诊室的酮症酸中毒。25%的新发1型糖尿病(T1D)患者表现为糖尿病在T1D Exchange注册表中，酮症酸中毒为COVID19+。我们的小组报告说，表现为糖尿病酮症酸中毒的新发2型糖尿病患者数量。这表明， COVID19的发病机制可能对胰岛β细胞功能有急性和特异性的影响。其中一个了解SARS-CoV2感染如何影响患者的β细胞功能和生存的障碍是可供研究的生理相关动物模型数量有限。我们利用了独特的访问建立SCV2免疫动物胰腺模型并了解感染对胰岛β细胞功能的影响和生存。我们的初步数据显示：(1)SARS-CoV2直接感染β细胞，(2)SARS-CoV2 感染引起胰岛形态显著改变；(3)SARS-CoV2感染改变胰岛β细胞代谢糖酵解；(4)SARS-CoV2感染导致β细胞功能和存活率下降。这项提案的目标是定义驱动急性后后果的机制柯萨奇病毒19介导的体内β细胞损伤。关于SARS-CoV2是否存在文献争议直接感染β细胞并影响β细胞的功能和存活，或者如果葡萄糖稳态的破坏病人是次要的。我们假设SARS-CoV2感染重新编程细胞新陈代谢和导致坏死性下垂，从而使宿主急性期和急性期后易受β细胞功能障碍的影响柯萨奇病毒19的后遗症。这些高度创新的实验利用了一种独特的、与临床相关的模型系统，并使用尖端技术来评估β细胞的存活和代谢是如何受到 SARS-CoV2感染。这些实验将提供关键的机械洞察，以支持新出现的急性高血糖、糖尿病酮症酸中毒和潜在终生糖尿病的临床表型可能会影响相当数量的从COVID19康复的患者。