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：
10351622
负责人：
David W Gludish
金额：
$ 15.48万
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/10351622
关键词：
2019-nCoV ACE2 Acute Alveolar Alveolar Macrophages Alveolus Anatomy 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 Communicable Diseases Comparative Pathology Coronavirus Cues Cultured Cells DNA Discipline Disease Disease Progression Drug Targeting Enterobacteria phage P1 Cre recombinase Environment Epithelial Faculty Focal Infection Functional disorder Funding Growth HIV Histologic Histopathology Human Hyaluronan Immune Immunology Impairment In Vitro Infection Inflammation Interferons Intervention Investigation Laboratories Learning Length Longitudinal Studies Lung Lung diseases 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 Proteins Publishing Pulmonary Inflammation Pulmonary Pathology RNA RNA Polymerase II RNA-Directed RNA Polymerase Recovery Replicon Reporter Reporting Research Respiratory Failure Route SARS-CoV-2 infection SARS-CoV-2 pathogenesis Science Scientist Seeds Severity of illness Societies Stimulus System Testing Therapeutic Time Training Universities Variant Vero Cells Veterinarians Veterinary Medicine Viral Viral Pathogenesis Viral Proteins Virion Virus Virus Diseases Virus Replication Virus Shedding Work base body system career cellular engineering 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 macrophage 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 virus envelope

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.

该申请寻求支持研究重点的兽医，从事独立职业翻译兽医科学家。申请人的提议研究巨噬细胞作为SARS-COV2-的驱动因素引起人类和小鼠模型的肺损伤，并将开发新的指标小鼠以报告SARS-COV2 小鼠的细胞靶标。这种多学科方法汇集了肺部生物学领域的主要专家，巨噬细胞生物学，病毒学，小鼠遗传学和肺病理学。在康奈尔大学学院兽医医学，申请人将在博士的实验室中进行研究。大卫·罗素（David Russell）和赫克托（Hector）博士 Aguilar-Carreño（微生物学和免疫学系），组织病理学分析在 Gerald Duhamel博士（生物医学科学系）实验室。用于肺部的特定动手培训上皮维修分析，申请人将在卡拉·金博士（哈佛医学）的实验室工作学校/儿童医院波士顿）。主要导师罗素博士是巨噬细胞生物学及其专家与几种肺病原体的相互作用，尤其是M. toberculcolosis和HIV。他在训练方面有良好的记录通过联邦研究资助，后者兽医科学家一直担任终身任职职位。 Aguilar-Carreño博士广泛发表了有关包围病毒的入口和出口，重点是 Paramyxoviruses，最近改编了他描述的鼠标挑战平台，用于抗病毒和疫苗发现，朝向SARS-COV2。 Duhamel博士是兽医解剖病理学家，研究重点传染病，包括小鼠的肺病原体。最后，Carla Kim博士是肺上皮修复的先驱和干细胞生物学。在拟议的工作中增加广度和深度，申请人组装了一个团队热情的合作者（与两名练习MD医生一起），包括老鼠遗传学和肺部领导者受伤（Kahn和Morrisey博士），透明质酸生物学（Hascall博士）和人类肺病理学（博士 Borczuk）。康奈尔大学的研究环境在传染病和比较病理学，而DRS的组合专家。 Kim和Borczuk添加了强烈的翻译和集成关注肺泡损伤的驱动因素。该提案将调查居民和招募的方式在小鼠SARS-COV2期间，巨噬细胞失调，是否取决于直接病毒感染巨噬细胞或环境提示。在AIM 1中，将生成记者小鼠以识别SARS-COV2- 感染过程中感染细胞和不对称恢复。在AIM 2期间，巨噬细胞子集的性质由于病毒靶标将进行研究，并且它们由Dr.开发的测定法确定的功能缺陷确定。罗素。在AIM 3中，在人类ACE2的小鼠中进行病毒挑战研究将询问巨噬细胞作为驱动因素肺泡损伤，并测试巨噬细胞干预是否改善了小鼠的临床结果。候选人将作为微生物学系高级研究助理开始这项研究和免疫学（75％的研究工作），在独立奖励阶段有预期的初级教师过渡。