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Novel animal models to dissect how lung macrophages contribute to SARS-CoV2 alveolar pathology and respiratory failure

新型动物模型可剖析肺巨噬细胞如何导致 SARS-CoV2 肺泡病理和呼吸衰竭

基本信息

批准号：
10533375
负责人：
David W Gludish
金额：
$ 15.36万
依托单位：
CORNELL UNIVERSITY
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：
2021-12-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10533375
关键词：
2019-nCoV ACE2 Acute Alveolar Alveolar Macrophages Alveolus Animal Model Animals Award Behavior Biological Assay Biology Boston COVID-19 severity COVID-19 susceptibility Cell Death Cells Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Communicable Diseases Comparative Pathology Coronavirus Cues Cultured Cells DNA Discipline Disease Disease Progression Drug Targeting Engineering Enterobacteria phage P1 Cre recombinase Environment Epithelium Faculty Focal Infection Functional disorder Funding Growth HIV HIV/TB Histologic Histopathology Human Hyaluronan Immune Immunology Impairment In Vitro Infection Inflammation Interferons Intervention Investigation Laboratories Learning Length Longitudinal Studies Lung Lung diseases Macrophage Maps Measures Mentors Microbiology Molecular Mus Mycobacterium tuberculosis Nature Neutralization Tests Neutralizing antibody assay Organ Organoids Outcome Output Paramyxovirus Pathogenicity Pathologist Pathology Pediatric Hospitals Peptide Hydrolases Pharmaceutical Preparations Phase Phenotype Physicians Positioning Attribute Post-Acute Sequelae of SARS-CoV-2 Infection Postdoctoral Fellow Predisposition Productivity Proteins Publishing Pulmonary Inflammation Pulmonary Pathology RNA RNA-Directed RNA Polymerase Recovery Replicon Reporter Reporting Research Respiratory Failure Route SARS-CoV-2 infection SARS-CoV-2 pathogenesis Science Scientist Severity of illness Societies Stimulus System Testing Therapeutic Time Training Universities Variant Vero Cells Veterinarians Veterinary Anatomy Veterinary Medicine Viral Viral Pathogenesis Viral Proteins Virion Virus Virus Diseases Virus Replication Virus Shedding Work body system career cellular targeting clinically relevant college epithelial repair high throughput screening human model improved in vivo interdisciplinary approach interest long-term sequelae lung injury lung pathogen lung repair medical schools member monocyte mouse genetics mouse model novel pandemic disease pneumocyte post SARS-CoV-2 infection post-doctoral training prevent recruit repaired respiratory stem cell biology tenure track tool transcriptomics vaccine discovery viral RNA virology

项目摘要

This application seeks support for a research-emphasis veterinarian embarking on an independent career as a translational veterinarian-scientist. The applicant proposes to study macrophages as drivers of SARS-CoV2- induced lung damage in humans and mouse models, and will develop novel indicator mice to report SARS-CoV2 cellular targets in mice. This multi-disciplinary approach brings together leading experts in lung biology, macrophage biology, virology, mouse genetics and pulmonary pathology. At Cornell University College of Veterinary Medicine, the applicant will perform research in the laboratories of Drs. David Russell and Dr. Hector Aguilar-Carreño (Department of Microbiology and Immunology), with histopathology analyses performed in the laboratory of Dr. Gerald Duhamel (Department of Biomedical Sciences). For specific hands-on training in lung epithelial repair assays, the applicant will work in the laboratory of Dr. Carla Kim (Harvard Medical School/Children’s Hospital Boston). Dr. Russell, primary mentor, is an expert in macrophage biology and their interaction with several lung pathogens, notably M.tuberculosis and HIV. He has a proven track record in training post-doctoral veterinarian-scientists that have gone on to tenure-track positions with federal research funding. Dr. Aguilar-Carreño has published extensively on the entry and egress of enveloped viruses with emphasis on paramyxoviruses, and recently has adapted his well-described mouse challenge platform for antiviral and vaccine discovery, toward SARS-CoV2. Dr. Duhamel is a veterinary anatomic pathologist with a research focus in infectious disease, including lung pathogens in mice. Finally, Dr. Carla Kim is a pioneer in lung epithelial repair and stem cell biology. Adding breadth and depth to the proposed work, the applicant has assembled a team of enthusiastic collaborators (with two practicing MD physicians), including leaders in mouse genetics and lung injury (Drs. Kahn and Morrisey), hyaluronan biology (Dr. Hascall), and human pulmonary pathology (Dr. Borczuk). The research environment at Cornell is exceptional in the disciplines of infectious disease and comparative pathology, while the combined expertise of Drs. Kim and Borczuk adds a strong translational and integrative focus on drivers of alveolar damage. The proposal will probe how resident and recruited macrophages are dysregulated during SARS-CoV2 in mice, whether dependent on direct viral infection of macrophages or on environmental cues. In Aim 1, reporter mice will be generated to identify SARS-CoV2- infected cells during infection and upon asymptomatic recovery. During Aim 2, the nature of macrophage subsets as viral targets will be studied, and their resulting functional deficits determined using assays developed by Dr. Russell. In Aim 3, viral challenge studies in human Ace2-expressing mice will interrogate macrophages as drivers of alveolar damage, and test whether macrophage interventions improve clinical outcomes in mice. The candidate will begin this research as Senior Research Associate in the Department of Microbiology and Immunology (75% research effort), with an expected junior faculty transition in the independent award phase.

此应用程序寻求支持的研究重点兽医走上独立的职业生涯，翻译兽医科学家申请人建议研究巨噬细胞作为SARS-CoV 2的驱动因素，在人类和小鼠模型中诱导肺损伤，并将开发新的指示小鼠来报告SARS-CoV 2 细胞靶点。这种多学科方法汇集了肺部生物学领域的领先专家，巨噬细胞生物学、病毒学、小鼠遗传学和肺病理学。在康奈尔大学兽医，申请人将在大卫罗素博士和赫克托博士的实验室进行研究 Aguilar-Carreño（微生物学和免疫学系），组织病理学分析在 Gerald Duhamel博士的实验室（生物医学科学系）。针对肺部的具体实践培训上皮修复试验，申请人将在Carla Kim博士（哈佛医学中心）的实验室工作波士顿儿童医院（Children's Hospital Boston）罗素博士，主要导师，是巨噬细胞生物学和他们的专家。与几种肺部病原体的相互作用，特别是结核分枝杆菌和艾滋病毒。他在训练方面有着良好的记录获得联邦研究基金的博士后兽医科学家。博士Aguilar-Carreño发表了大量关于包膜病毒进出的文章，重点是副粘病毒，最近已经调整了他的良好描述的小鼠挑战平台，用于抗病毒和疫苗的发现，针对SARS-CoV 2。Duhamel博士是一位兽医解剖病理学家，感染性疾病，包括小鼠的肺部病原体。最后，卡拉·金博士是肺上皮修复的先驱和干细胞生物学为了增加拟议工作的广度和深度，申请人组建了一个热情的合作者（与两名执业MD医生），包括小鼠遗传学和肺损伤（Kahn和Morrisey博士）、透明质酸生物学（Hascall博士）和人类肺部病理学（Hascall博士）。 Borczuk）。康奈尔大学的研究环境在传染病学科中是例外的，比较病理学，而金博士和Borczuk的综合专业知识增加了强大的翻译和综合关注肺泡损伤的驱动因素。该提案将探讨如何居民和招募在SARS-CoV 2小鼠中，巨噬细胞在SARS-CoV 2期间失调，无论是否依赖于巨噬细胞或环境线索。在目标1中，将产生报告小鼠以鉴定SARS-CoV 2- 在感染期间和无症状恢复时感染的细胞。在目标2中，巨噬细胞亚群的性质将研究病毒靶点，并使用Dr. Russell.在目标3中，在表达人Ace 2的小鼠中进行的病毒攻击研究将询问巨噬细胞作为驱动因子的肺泡损伤，并测试巨噬细胞干预是否改善小鼠的临床结果。的候选人将开始这项研究作为高级研究助理在微生物学系，免疫学（75%的研究工作），预计在独立奖励阶段的初级教师过渡。