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

此申请旨在为一名注重研究的兽医开始独立的职业生涯寻求支持 翻译兽医兼科学家。申请人建议研究巨噬细胞作为SARS-CoV2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-CoV2 小鼠体内的细胞靶标。这种多学科的方法聚集了肺部生物学领域的顶尖专家， 巨噬细胞生物学、病毒学、小鼠遗传学和肺部病理学。在康奈尔大学学院 兽医，申请者将在大卫·拉塞尔博士和赫克托博士的实验室进行研究 Aguar-Carreño(微生物和免疫学系)，组织病理学分析在 Gerald Duhamel博士(生物医学科学系)的实验室。在肺部进行特定的动手训练 上皮修复测试，申请人将在Carla Kim博士(哈佛医学院)的实验室工作 学校/波士顿儿童医院)。罗素博士是主要导师，是巨噬细胞生物学和他们的 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。他在训练方面有过硬的记录 博士后兽医-已经获得终身教职的科学家-在联邦研究资金的支持下跟踪职位。 Aguar-Carreño博士发表了大量关于包膜病毒进出的文章，重点是 副粘病毒，最近修改了他著名的小鼠挑战平台，用于抗病毒和 疫苗发现，走向SARS-CoV2。杜哈梅尔博士是一名兽医解剖病理学家，专注于研究 在传染病方面，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，申请人组建了一个团队， 热情的合作者(与两名执业的MD医生)，包括小鼠遗传学和肺脏方面的领导者 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(Dr。 Borczuk)。康奈尔大学的研究环境在传染病和 比较病理学，而Kim博士和Borczuk博士的结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。该提案将调查常驻和招聘人员是如何 巨噬细胞在SARS-CoV2期间的调节失调是否依赖于病毒的直接感染 巨噬细胞或环境信号。在目标1中，将产生报告小鼠来识别SARS-CoV2- 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 作为病毒的靶点将被研究，并使用Dr。 拉塞尔。在目标3中，在表达人血管紧张素转换酶2的小鼠中进行的病毒挑战研究将询问巨噬细胞作为驱动因素 并测试巨噬细胞干预是否能改善小鼠的临床结果。这个 候选人将以微生物学系高级研究助理的身份开始这项研究 免疫学(75%的研究工作)，预计初级教员将在独立颁奖阶段过渡。

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.