Administrative Supplement to CGRP's effect on hearing and balance in a mouse model of migraine

CGRP 对偏头痛小鼠模型听力和平衡影响的行政补充

• 批准号: 10173048
• 负责人: ANNE E LUEBKE
• 金额: $ 19.25万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173048
• 关键词: 2019-nCoV; Administrative Supplement; Animals; Antibodies; Biological Assay; Body Weight decreased; COVID-19; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cause of Death; Cessation of life; Chills; Control Groups; Coughing; Development; Disease; Emetics; Equilibrium; Exhibits; Exposure to; Fatigue; Fever; Future; Headache; Hearing; Human; Immune response; Infection; Interleukin-6; K-18 conjugate; Low Grade Fever; Measures; Migraine; Modeling; Motion; Mus; Nausea; Neuroimmune; Pain; Patients; Peptidyl-Dipeptidase A; Pharmacologic Substance; Phase II Clinical Trials; Production; Rattus; Reaction; Research; Risk; SARS coronavirus; Severities; Shortness of Breath; Shrews; Siblings; Smell Perception; Sore Throat; Sputum; Symptoms; TRP channel; Temperature; Testing; Therapeutic; Transgenic Animals; Transgenic Mice; Transgenic Organisms; Vaccines; Viral; Viral Load result; Virus; Vomiting; associated symptom; base; coronavirus disease; cytokine release syndrome; flu; humanized mouse; in vivo; induced hypothermia; mouse model; neuroinflammation; novel; parent grant; phase III trial; pre-clinical; respiratory; response; therapeutic target

The purpose of this COVID-19 research supplement is to critically evaluate if a calcitonin gene-related peptide (CGRP) receptor antagonist can mitigate both neuroinflammatory and hyper-immune responses to SARS-CoV-2 infection. In December 2019, the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) was identified. There are now over ~5.5 million confirmed cases worldwide (1.6 million US), and 345,000 deaths (~100,000 US). COVID-19 causes a respiratory illness like the flu with symptoms such as fever, cough, loss of smell, fatigue, sputum production, shortness of breath, sore throat, headache, chills, and nausea or vomiting. Approximately 80% of people have mild disease and recover. However, in those remaining 20%, COVID-19 is severe and there is evidence that progression to the most serious type of COVID-19 illness is related to a hyper-immune response (ie, cytokine storm). Currently, there are no effective vaccines or treatments available for COVID-19. In this supplement we will test the ability of CGRP-receptor antagonists to inhibit the neuroimmune consequences of SARS-CoV-2 infection, using temperature and nausea as an indicator of SARS-CoV2 infection, as we are doing in our parent grant to assess migraine nausea pain. A humanized mouse model has been developed for studying SARS-CoV2, where mice express the human angiotensin-converting enzyme 2 (hACE2), enabling us to model Covid-19 in the mouse. The FDA has recently approved Biohaven Pharmaceuticals to proceed to a phase 2 clinical trial of its CGRP-receptor antagonist (vazegepant; currently in phase 3 trials for migraine) to treat patients with severe COVID-19, suggesting that the neuroinflammatory reaction that is initiated by CGRP in response to SARS- CoV2 could be a therapeutic target for treating severe Covid-19, and that the non-invasive readouts of neuroinflammation that we are developing could be used to rapidly identify at risk patients. Our hypothesis is that mild to severe COVID-19 symptoms will occur in the transgenic hACE2 mouse that has been infected with SARS-CoV-2, and that a CGRP receptor antagonist will mitigate these symptoms. The specific aims are to test the following hypotheses that transgenic mice and non-carrier littermates infected with SARS-CoV-2 will exhibit: aim 1) mild severe symptoms based on viral load, and if these symptoms are less severe when treated with a CGRP-receptor antagonist; and aim 2) reduced fever and nausea-like pain when treated with a CGRP- receptor antagonist. Information gained from these studies will provide a direct assessment of whether a CGRP-receptor antagonist can mitigate both mild and severe symptoms associated with SARS-CoV-2 infection. This proposal also impacts the development of robust preclinical in vivo assays of COVID-19 symptoms, paving the way to develop and test future therapeutics for COVID-19.

该COVID-19研究补充的目的是批判性评估降钙素基因是否相关 肽（CGRP）受体拮抗剂可以减轻对神经炎症和超免疫反应 SARS-COV-2感染。 2019年12月，严重急性引起的冠状病毒病（Covid-19） 鉴定出呼吸综合征COV-2（SARS-COV-2）。现在有超过550万个确认案件 全球（美国160万）和345,000人死亡（约100,000美国）。 COVID-19会引起呼吸道疾病 流感症状，例如发烧，咳嗽，气味降低，疲劳，痰液产生，呼吸急促，酸痛 喉咙，头痛，发冷，恶心或呕吐。大约80％的人患有轻度疾病， 恢复。但是，在剩下的20％的人中，共vid-19是严重的，有证据表明向前发展 COVID-19疾病的最严重类型与超免疫反应有关（即细胞因子风暴）。现在， Covid-19没有有效的疫苗或治疗方法。在这种补充中，我们将测试能力 使用CGRP受体拮抗剂抑制SARS-COV-2感染的神经免疫性后果 温度和恶心为SARS-COV2感染的指标，就像我们在父母授予中所做的那样 评估偏头痛恶心疼痛。已经开发了用于研究SARS-COV2的人源化小鼠模型， 小鼠表达人血管紧张素转换酶2（HACE2），使我们能够在19号中进行建模 鼠标。 FDA最近已批准Biohaven Pharmaceuticals进行第二阶段临床试验 其CGRP受体拮抗剂（Vazegepant；目前正在偏头痛的第3阶段试验中）治疗严重患者 COVID-19，表明CGRP响应SARS-发起的神经炎症反应 COV2可能是治疗严重的Covid-19的治疗靶点，并且是非侵入性的读数 我们正在开发的神经炎症可用于快速识别风险患者。我们的假设是 在已感染的转基因HACE2小鼠中，这种轻度至重度的Covid-19症状将发生 SARS-COV-2，并且CGRP受体拮抗剂会减轻这些症状。具体目的是 测试以下假设，即感染了SARS-COV-2的转基因小鼠和非携带者同窝材料将 展品：目标1）基于病毒负荷的轻度严重症状，如果治疗时这些症状不那么严重 与CGRP受体拮抗剂；和目标2）用CGRP治疗时的发烧和恶心样疼痛 受体拮抗剂。从这些研究中获得的信息将直接评估是否 CGRP受体拮抗剂可以减轻与SARS-COV-2相关的轻度和重度症状 感染。该提案还影响了COVID-19的鲁棒临床前分析的发展 症状，为开发和测试Covid-19的未来治疗剂铺平了道路。