RAPID: Transcription Factor Profiling for SARS-CoV2 Tolerance/Symbiosis Regulation

RAPID：SARS-CoV2 耐受/共生调节的转录因子分析

• 批准号: 2031624
• 负责人: Thomas Gilmore
• 金额: $ 20万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2031624&HistoricalAwards=false
• 关键词: RAPID; Transcription; Factor; Profiling; SARS

This research will provide increased knowledge of the molecular factors enabling different hosts (especially bats vs. humans) to tolerate the recently emergent SARS-Cov-2 coronavirus. This project will use bat cell line models to investigate differences in cellular proteins which lead to differences in immunity profiles of cells from the different species. The proposed research will identify proteins that are differentially active in different cell line models, and the effects that immune-stimulating factors and SARS-CoV-2 proteins have on host cell protein activities. Results from this research could lead to new insights into why and how certain viruses, in particular SARS-CoV-2, can be tolerated in some species (e.g., bats) but not others (e.g., humans), and could provide information for the emergence of future viruses that can cause pandemics in animal and human populations. The interdisciplinary research team comprises three experienced lead scientists with expertise in complementary areas of research. In addition, the research will provide training to two graduate students who will be able to pursue careers in related areas in academia, the private sector, or government.The goal of this research is to further knowledge of the molecular processes that underlie species-specific infection of cells with SARS-CoV2. This research will provide insights into transcription factor-based differences between host cells of bat origin, which can tolerate SARS-CoV2 infection in a non-pathogenic manner, vs human and other bat cells that do not show this tolerance. The research involves the collaboration of three PIs with complementary approaches that they will bring to this project. Five major experimental goals will be addressed: 1) characterization of transcriptional and nuclear proteomic profiles that distinguish different bat cell lines; 2) use of a novel protein-binding microarray to profile active transcription factors among these cell lines; 3) characterization of candidate immunity transcription factors, such as NF-κB and IRFs, that are likely different between SARS-CoV2 tolerant and susceptible cell lines; 4) effects of SARS-CoV2 gene products on identified transcription factors in the various cell lines; and 5) potential for replication of novel SARS-CoV2 tracer viruses in different bat cell lines. The proposed research will increase knowledge of SARS-SoV-2 biology. In addition, it investigates the hypothesis that bat cells have evolved molecular immunity pathways that promote or lead towards tolerance (perhaps even symbiosis) of bats with coronaviruses. Such information may lead to the identification of therapeutics for humans and animals against coronaviruses. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项研究将提供更多关于使不同宿主(特别是蝙蝠与人类)耐受最近出现的SARS-CoV-2冠状病毒的分子因素的知识。该项目将使用BAT细胞系模型来研究细胞蛋白质的差异，这些差异导致不同物种细胞免疫图谱的差异。这项拟议的研究将确定在不同细胞系模型中具有不同活性的蛋白质，以及免疫刺激因子和SARS-CoV-2蛋白质对宿主细胞蛋白质活性的影响。这项研究的结果可能导致对某些病毒，特别是SARS-CoV-2为什么以及如何在某些物种(例如蝙蝠)中可以容忍，而在另一些物种(例如人类)中不能容忍的新见解，并可能为未来出现可能导致动物和人类种群大流行的病毒提供信息。跨学科研究小组由三名经验丰富的首席科学家组成，他们在互补的研究领域拥有专门知识。此外，这项研究将为两名研究生提供培训，他们将能够在学术界、私营部门或政府部门从事相关领域的职业生涯。这项研究的目标是进一步了解导致SARS-CoV2感染细胞的特定物种的分子过程。这项研究将提供关于蝙蝠来源的宿主细胞与人类和其他不表现出这种耐受性的蝙蝠细胞之间基于转录因子的差异的见解。蝙蝠来源的宿主细胞可以以非致病方式耐受SARS-CoV2感染。这项研究涉及三个私人投资机构的合作，他们将把互补的方法带到这个项目中。将致力于五个主要的实验目标：1)区分不同BAT细胞系的转录和核蛋白质组特征；2)使用新型的蛋白质结合微阵列来描述这些细胞系中的活性转录因子；3)鉴定候选免疫转录因子，如NF-κB和IRF，它们可能在SARS-CoV2耐受和敏感细胞系中不同；4)SARS-CoV2基因产物对不同BAT细胞系中已确定的转录因子的影响；以及5)新型SARS-CoV2示踪病毒在不同BAT细胞系中复制的可能性。这项拟议的研究将增加对SARS-SOV-2生物学的了解。此外，它还研究了一种假设，即蝙蝠细胞进化了分子免疫途径，促进或导致蝙蝠对冠状病毒的耐受(甚至共生)。这些信息可能会导致人类和动物对抗冠状病毒的治疗方法的确定。这一快速奖项是由综合组织系统生物部的生理和结构系统集群利用冠状病毒援助、救济和经济安全(CARE)法案的资金颁发的。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。