Mechanisms for post-COVID pituitary damage

新冠病毒后垂体损伤的机制

基本信息

批准号：
10683355
负责人：
Takako Araki
金额：
$ 39.15万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2021-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683355
关键词：
2019-nCoV ACE2 Acute Address Admission activity Adult Affect Appearance Autopsy Blood Brain COVID-19 COVID-19 complications COVID-19 mortality COVID-19 patient COVID-19 survivors Cell Lineage Cells Chronic Fatigue Syndrome Cities Clinical Clinical Research Complication Development Diagnosis Disease Endocrine Evaluation Fatigue Female Fibrin fragment D Formalin Foundations Functional disorder Gene Expression Genes Genetic Genetic Transcription Genomics Guidelines Health Health Care Costs Healthcare Histologic Hormones Hospital Referrals Hospitalization Hour Human Hypopituitarism Hypotension Immune Immune system Immunofluorescence Immunologic In Situ Individual Infection Inflammation Interleukin-6 Invaded Length of Stay Long COVID Longitudinal Studies Los Angeles Measures Medical center Messenger RNA Molecular Analysis Myocardial dysfunction New York City Outcome Paraffin Embedding Participant Patients Pituitary Gland Pituitary Hormones Population Process Public Health Quality of life Questionnaires Reporting Research Risk SARS coronavirus SARS-CoV-2 infection Selection for Treatments Severe Acute Respiratory Syndrome Site Sleep disturbances Southeastern Asia Structure Symptoms Syndrome System TNF gene Technology Testing Tissue Embedding Tissues Visit acute infection cancer immunotherapy cell stroma cell type cognitive function cytokine cytokine release syndrome digital evidence base experience follow-up functional decline growth hormone deficiency health management high resolution imaging hormone deficiency imaging system immune activation immunoreaction inflammatory marker innovation lactotroph mRNA Expression male novel pandemic disease patient subsets pituitary gland development post-COVID-19 prevent protocol development receptor societal costs standard of care success timeline

项目摘要

PROJECT SUMMARY COVID-19–related extra-pulmonary damage is common and may even be observed in patients with mild COVID- 19 symptoms. There is an urgent and immediate need to establish optimal post-infection health care strategies for these patients, yet mechanisms underlying their appearance remain unexamined. For example, post-COVID- 19 chronic fatigue syndrome has been reported in 54% of COVID-19 survivors, including those without severe symptoms during the acute infection; however, its cause has not been addressed. Post-COVID-19 chronic fatigue syndrome’s symptoms mimic those experienced by patients with well-described pituitary hormone deficiencies, supporting the concept that pituitary dysfunction in patients with COVID-19 may be implicated in post–COVID-19 health complications. Several lines of evidence support the premise that SARS-CoV-2 infection damages the pituitary, leading to disrupted pituitary function. First, we detected expression of the SARS-CoV-2 receptor ACE2 in the normal human pituitary by immunofluorescence, suggesting that SARS-CoV-2 may directly damage pituitary endocrine cells. Second, it has been reported that the SARS pandemic in Southeast Asia in 2002, by SARS-CoV-1, caused post-infection pituitary function decline, although direct damage to the pituitary was not investigated. Third, clinical observations suggest that patients with COVID-19 show aberrant immune activity and may develop cytokine storm, with particularly acute elevations of IL-6 and TNFα. Cytokine storm, which can occur as a consequence of with cancer immunotherapy treatment, for example, is frequently associated with pituitary inflammation and dysfunction, although the detailed pathogenetic mechanisms are not known. This suggests that aberrant activation of the immune system may also indirectly damage the pituitary in patients with COVID-19. Elucidating the mechanisms underlying direct and indirect pituitary damage related to SARS-CoV-2 infection is critical to establishing guidelines for timely diagnosis and management of pituitary dysfunction in COVID-19 survivors. In Aim 1, we will determine whether SARS-CoV-2 directly invades the pituitary and causes pituitary structural damage. We will study autopsy-derived pituitary tissues obtained from COVID-19 deceased patients and normal control pituitary tissues. Moreover, using a novel spatial genomics technology, we will determine changes in gene expression associated with COVID-19 in each of the five pituitary endocrine lineages and stroma cells. In Aim 2, we will determine the association and the timeline of pituitary dysfunction and symptoms in patients who were infected by SARS-CoV-2. By combining detailed and innovative cellular and molecular analyses, and clinical studies, we will identify the mechanisms responsible for pituitary dysfunction in COVID-19 patients and determine the course of pituitary dysfunction in COVID-19. These innovative studies will, in turn, enable the development of an evidence-based clinical guide for evaluation and management of hormone deficiencies in the vast COVID-19 population across the globe.

项目摘要相关-19相关的肺外损伤是常见的，甚至可能在轻度共同的患者中观察到 19症状。迫切需要立即建立最佳的感染后医疗保健策略对于这些患者而言，其外观背后的机制仍未受到检查。例如，杂化后 - 据报道，在54％的COVID-19表面表面上有19个慢性疲劳综合征，其中包括没有严重的情况急性感染期间的症状；但是，其原因尚未得到解决。牛后19慢性疲劳综合征的符号模仿了垂体激素的患者经历的符号缺陷，支持以下概念，即可能与19009例患者的垂体功能障碍有关循环后-19健康并发症。几条证据支持SARS-COV-2感染的前提损坏垂体，导致垂体功能中断。首先，我们检测到SARS-COV-2的表达免疫荧光中正常人垂体中的受体ACE2，这表明SARS-COV-2可能直接损害垂体内分泌细胞。其次，据报道，东南亚的SARS大流行 2002年，SARS-COV-1造成感染后垂体功能下降，尽管直接损害了垂体第三，临床观察结果表明，COVID-19患者表现出异常免疫活性并可能发展为细胞因子风暴，特别是IL-6和TNFα的急性升高。细胞因子风暴，例如，由于癌症免疫疗法治疗而发生的可能发生尽管详细的致病机制不是垂体注射和功能障碍相关的已知。这表明免疫系统的异常激活也可能间接损害垂体 Covid-19患者。阐明与 SARS-COV-2感染对于建立及时诊断和管理指南至关重要 COVID-19-19中冲浪者的功能障碍。在AIM 1中，我们将确定SARS-COV-2是否直接入侵垂体和垂体结构损害。我们将研究从尸检衍生的垂体时机 COVID-19已故患者和正常对照垂体时间。而且，使用一种新型的空间基因组学技术，我们将确定在五个垂体中的每一个中，与Covid-19相关的基因表达变化内分泌谱系和基质细胞。在AIM 2中，我们将确定垂体的关联和时间表被SARS-COV-2感染的患者的功能障碍和符号。通过结合详细和创新的细胞和分子分析以及临床研究，我们将确定负责垂体的机制 COVID-19患者的功能障碍，并确定COVID-19的垂体功能障碍的过程。这些创新研究将依次制定基于证据的临床指南，以进行评估和在全球范围内广泛的Covid-19人口中的马匹缺乏治疗。