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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

基本信息

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
项目类别：
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

项目摘要

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.

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