Innate Control of Adaptive Immunity to SARS-CoV-2

对 SARS-CoV-2 的适应性免疫的先天控制

• 批准号: 10630134
• 负责人: Benjamin Goldman-Israelow
• 金额: $ 19.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630134
• 关键词: 1918 influenza pandemic; 2019-nCoV; Acute; Adjuvant; Advisory Committees; Antibodies; Antibody Formation; Antibody titer measurement; B-Lymphocytes; COVID-19; COVID-19 mortality; Cells; Cessation of life; Communicable Diseases; Complex; Coronavirus; DNA; Data; Dendritic Cells; Development; Doctor of Medicine; Doctor of Philosophy; Etiology; Fellowship Program; Future; Genotype; Goals; Grooming; Hospitals; Humoral Immunities; IFNAR1 gene; Immune; Immune response; Immune signaling; Immunity; Immunobiology; Immunoglobulin A; Immunologics; Immunology; Infection; Influenza A Virus, H1N1 Subtype; Influenza A virus; Infrastructure; Innate Immune Response; Innate Immune System; Interferon Type I; Interferons; Internal Medicine; Journals; Kinetics; Knowledge; Laboratories; Lead; Licensing; Location; Medicine; Mentors; Mentorship; Methods; Molecular Virology; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Natural Immunity; Pathology; Pathway interactions; Pattern recognition receptor; Physicians; Principal Investigator; Production; Productivity; Program Development; Publishing; RNA; Receptor Signaling; Records; Research; Research Personnel; Residencies; Resources; Role; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; Science; Scientist; Shapes; Signal Transduction; T-Lymphocyte; Training; Training Programs; Vaccination; Vaccines; Viral; Viral Respiratory Tract Infection; Virus; Virus Diseases; Wild Type Mouse; Work; Writing; ZIKA; adaptive immune response; adaptive immunity; career; career development; cell type; coronavirus disease; coronavirus vaccine; cytokine; design; efficacy evaluation; human coronavirus; immune activation; immunopathology; improved; inhibiting antibody; medical schools; mouse model; mucosal vaccination; mucosal vaccine; pandemic disease; pandemic response; pathogen; receptor; respiratory virus; response; sensor; tool; translational scientist; vaccine development; vaccine trial

Project Summary/Abstract To date, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) has caused over 32 million cases of coronavirus disease (COVID-19), with ~1 million associated deaths. Multiple vaccine trials have begun in an effort to stop this pandemic, yet the correlates of viral clearance and immune protection from SARS-CoV-2 remain unknown. In fact, there are no licensed vaccines to any human coronavirus, as we have not yet discovered the immunologic correlates of a successful coronavirus vaccine. In his brief tenure in the Iwasaki lab, Dr. Goldman-Israelow has already developed a highly adaptable mouse model of SARS-CoV-2 infection that can be applied to mice of any genotype. He published this work as co-first author in the Journal of Experimental Medicine. He also showed that innate immune activation drives acute pathology. However, the extent to which innate immune signals drive adaptive immunity remains to be explored. This proposal will address how: (1) type I interferon signaling and (2) cGAS signaling control antibody development to SARS- CoV-2. This work is critical for characterizing the fundamental rules that govern adaptive immunity to SARS- CoV-2, which will promote the development of highly effective vaccines. This proposal describes a rigorous five-year career development training program for Benjamin Goldman- Israelow, M.D., Ph.D., with the goal of preparing him for an independent research career as an academic physician-scientist. The principal investigator is a physician scientist who completed his M.D. and Ph.D. training in Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, where he studied molecular virology. Dr. Goldman-Israelow continued his training by joining the Physician Scientist Research Pathway at Yale New Haven Hospital, a combined residency and fellowship program, and is currently an infectious diseases fellow. He has embarked on an intensive training program to broaden his expertise in viral immunology under the mentorship of Dr. Akiko Iwasaki, a pioneer and world leader in deciphering the complex interplay among viruses, innate immune recognition, and adaptive immunity. Dr. Iwasaki is not only a world- class scientist, but also a world-class mentor with a very productive track record of mentoring physician- scientists. In addition to the intellectual grooming and practical laboratory-based training that Dr. Goldman- Israelow will continue to receive in Dr. Iwasaki’s lab, he has developed a training program built on high-yield didactic coursework. He has also carefully crafted an advisory committee comprising translational scientists with a broad range of scientific expertise relevant to this proposal and impressive records of mentorship. Yale School of Medicine, along with its Departments of Internal Medicine and Immunobiology, will provide the resources, support, and infrastructure to assist Dr. Goldman-Israelow in achieving the aims described in this proposal and his long-term goal of developing into an independent physician-scientist studying the rules that govern antibody development to both viral infection and vaccination.

项目概要/摘要 迄今为止，严重急性呼吸系统综合症冠状病毒 2 (SARS-Cov-2) 已导致超过 3200 万人感染 多项疫苗试验已导致约 100 万人死亡。 为阻止这一流行病而开始，但病毒清除和免疫保护的相关性 事实上，目前还没有针对任何人类冠状病毒的疫苗获得许可。 在他短暂的任期内尚未发现成功的冠状病毒疫苗的免疫学相关性。 岩崎实验室的 Goldman-Israelow 博士已经开发出一种高度适应性的 SARS-CoV-2 小鼠模型 他以共同第一作者的身份在《Journal of the Journal of Medicine》上发表了这项研究成果。 实验医学。他还表明，先天免疫激活会导致急性病理。 先天免疫信号在多大程度上驱动适应性免疫仍有待探讨。 解决如何：(1) I 型干扰素信号传导和 (2) cGAS 信号传导控制针对 SARS-的抗体开发 这项工作对于描述 SARS 适应性免疫的基本规则至关重要。 CoV-2，这将促进高效疫苗的开发。 该提案描述了本杰明·戈德曼严格的五年职业发展培训计划—— Israelow，医学博士、博士，目标是为他作为一名学者的独立研究生涯做好准备 首席研究员是一位完成医学博士和博士学位的医学科学家。 在西奈山伊坎医学院接受生物医学科学培训，在那里他学习分子 Goldman-Israelow 博士通过加入医师科学家研究途径继续接受培训。 耶鲁纽黑文医院是一个综合住院医师和研究金项目，目前是一家传染病医院 他已经开始了强化培训计划，以扩大他在病毒方面的专业知识。 在破译该复合物的先驱和世界领导者 Akiko Iwasaki 博士的指导下进行免疫学研究 病毒、先天免疫识别和适应性免疫之间的相互作用，岩崎博士不仅是一个世界- 一流的科学家，也是一位世界级的导师，在指导医生方面有着非常富有成效的记录—— 除了戈德曼博士提供的智力培训和基于实验室的实用培训之外， Israelow将继续在Iwasaki博士的实验室接受治疗，他开发了一个基于高产的培训计划 他还精心组建了一个由转化科学家组成的咨询委员会。 拥有与该提案相关的广泛科学专业知识和令人印象深刻的耶鲁指导记录。 医学院及其内科和免疫生物学系将提供 协助 Goldman-Israelow 博士实现本文所述目标的资源、支持和基础设施 提案以及他发展成为一名独立的医师科学家的长期目标，研究这些规则 控制病毒感染和疫苗接种的抗体发育。