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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：
10505064
负责人：
Senta K Georgia
金额：
$ 58.48万
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/10505064
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 Cohort Studies 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 Prevalence Primates Recovery Registries Reporting Reproducibility Resolution Respiratory System SARS-CoV-2 infection 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 methylation pattern nonhuman primate post-transplant prevent 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.

项目摘要 β细胞功能障碍和死亡是2型糖尿病发展的重要病理基础。我们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- CoV 2驱动的COVID 19大流行，有报告称成年COVID 19+患者出现糖尿病酮症酸中毒在急诊室25%的新发1型糖尿病（T1 D）患者表现为糖尿病 T1 D交换登记中的酮症酸中毒为COVID 19+。我们的小组报告说，出现糖尿病酮症酸中毒的新发2型糖尿病患者数量。这表明 COVID 19的发病机制可能对胰腺β细胞功能具有急性和特异性影响。之一理解SARS-CoV 2感染如何影响β细胞功能和患者生存的障碍是研究的生理学相关动物模型数量有限。我们利用了独特的访问权限，接种SCV 2的动物的胰腺进行建模，并了解感染如何影响β细胞功能和生存我们的初步数据表明：（1）SARS-CoV 2直接感染β细胞，（2）SARS-CoV 2 感染引起胰岛细胞形态学的显著变化，（3）SARS-CoV 2感染改变β细胞代谢（4）SARS-CoV 2感染导致β细胞功能和存活率下降。本提案的目的是确定导致急性期后后果的机制，体内COVID 19介导的β细胞损伤。关于SARS-CoV 2是否直接感染β细胞并影响β细胞功能和存活，或者如果葡萄糖稳态的破坏，病人是次要的。我们假设SARS-CoV 2感染重新编程细胞代谢，诱导坏死性凋亡，从而使宿主对β细胞功能障碍急性易感， COVID 19的后遗症。这些高度创新的实验利用了独特的临床相关模型系统，并采用尖端技术来评估β细胞的生存和代谢是如何受到影响， SARS-CoV 2感染。这些实验将提供关键的机械洞察力的基础，急性高血糖症、糖尿病酮症酸中毒和潜在终身糖尿病的新临床表型，可能会影响大量从COVID 19中康复的患者。