Mechanisms for post-COVID pituitary damage

新冠病毒后垂体损伤的机制

• 批准号: 10318857
• 负责人: Takako Araki
• 金额: $ 42.16万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10318857
• 关键词: 2019-nCoV; ACE2; Acute; Address; Admission activity; Adult; Affect; Appearance; Autopsy; Blood; Brain; COVID-19; COVID-19 mortality; COVID-19 patient; Cell Lineage; Cells; Chronic; Chronic Fatigue Syndrome; Cities; Clinical; Clinical Research; Complication; Cross-Sectional Studies; Development; Diagnosis; Disease; Endocrine; Evaluation; Fatigue; Female; Fibrin fragment D; Formalin; Foundations; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomics; Guidelines; Health; Health Care Costs; Healthcare; Histologic; Hormones; Hospital Referrals; Hour; Human; Hypopituitarism; Hypotension; Immune; Immune system; Immunofluorescence Immunologic; In Situ; Individual; Infection; Inflammation; Interleukin-6; Invaded; Length of Stay; Longitudinal Studies; Los Angeles; Lung; 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; Severe Acute Respiratory Syndrome; Site; Sleep disturbances; Southeastern Asia; Structure; Survivors; Symptoms; Syndrome; System; TNF gene; Technology; Testing; Time; TimeLine; Tissue Embedding; Tissues; Visit; acute infection; cancer immunotherapy; cell stroma; cell type; cognitive function; coronavirus disease; 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; prevent; protocol development; receptor; societal costs; standard of care; success

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.

项目总结 新冠肺炎相关的肺外损害很常见，甚至可能在轻度COVID患者中观察到。 19种症状。迫切需要建立最佳的感染后卫生保健战略 然而，对于这些患者，其外观背后的机制仍未得到研究。例如，后COVID- 据报道，54%的新冠肺炎幸存者患上了19种慢性疲劳综合症，包括那些没有严重 在急性感染期间出现症状；然而，其原因尚未解决。后新冠肺炎慢性 疲劳综合征的症状类似于脑下垂体激素患者的症状 缺乏，支持新冠肺炎患者的垂体功能障碍可能与 新冠肺炎事件后的健康并发症。有几条证据支持SARS-CoV-2感染 损害脑下垂体，导致脑下垂体功能紊乱。首先，我们检测了SARS-CoV-2的表达 免疫荧光法检测正常人脑垂体ACE2受体，提示SARS-CoV-2可能直接 损害脑下垂体内分泌细胞。第二，据报道，东南亚的SARS疫情在#年 2002年，由SARS-CoV-1引起的感染后垂体功能下降，虽然直接损害了垂体 没有被调查。第三，临床观察显示新冠肺炎患者表现出异常的免疫功能 并可能发展成细胞因子风暴，尤其是IL-6和肿瘤坏死因子α的急剧升高。细胞因子风暴， 例如，由于癌症免疫治疗的结果，经常会发生这种情况 与垂体炎和功能障碍有关，尽管详细的致病机制尚不清楚 为人所知。这表明，免疫系统的异常激活也可能间接损害脑垂体。 患有新冠肺炎的患者。直接和间接垂体腺损伤机制的阐明 SARS-CoV-2感染对建立及时诊断和治疗垂体的指南至关重要 新冠肺炎幸存者的功能障碍。在目标1中，我们将确定SARS-CoV-2是否直接入侵 并导致脑下垂体结构损伤。我们将研究从尸检中获得的脑下垂体组织 新冠肺炎死亡患者及正常对照脑垂体组织。此外，利用一种新的空间基因组学 技术上，我们将确定与新冠肺炎相关的基因在五个脑下垂体中的表达变化 内分泌谱系和基质细胞。在目标2中，我们将确定脑下垂体的联系和时间线 SARS-CoV-2感染患者的功能障碍和症状。通过将细节与创新相结合 细胞和分子分析以及临床研究，我们将确定脑下垂体的致病机制 新冠肺炎患者的垂体功能障碍，并确定新冠肺炎患者的垂体功能障碍的病程。这些 创新研究反过来将使以循证为基础的临床指南的开发成为可能， 全球新冠肺炎人群中荷尔蒙缺乏的管理。