Admin-Core-001

管理核心-001

• 批准号: 10710090
• 负责人: ANDREA L COX
• 金额: $ 11.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710090
• 关键词: 2019-nCoV; Address; Affect; Age; Antibodies; Antibody Response; Antigens; Basic Science; Biometry; COVID-19; COVID-19 patient; COVID-19 severity; Cell surface; Cells; Cessation of life; Clinical; Clinical Sciences; Collaborations; Communicable Diseases; Complement; Complex; Coupled; Data Analyses; Development; Diabetes Mellitus; Disease; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemiologic Monitoring; Epidemiology; Ethnic Origin; Evaluation; Flow Cytometry; Foundations; Gender; Goals; HIV; Health; Healthcare Systems; Heart Diseases; Human; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunology; Immunomodulators; Infant; Infection; Inflammasome; Inflammatory Response; Infrastructure; Interdisciplinary Study; International; Leadership; Mediating; Metabolic; Methods; Mission; Modeling; Monoclonal Antibody Therapy; Myeloid-derived suppressor cells; Organ Transplantation; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Peripheral Blood Mononuclear Cell; Persons; Population; Prospective cohort; Proteins; Protocols documentation; Public Health; Race; Reagent; Regimen; Reporting; Research; Research Activity; Research Personnel; Research Project Grants; Resources; Respiratory Tract Infections; Risk; SARS-CoV-2 antibody; SARS-CoV-2 immune response; SARS-CoV-2 immunity; SARS-CoV-2 infection; Sampling; Science; Serology; Serology test; Severity of illness; Sex Differences; Solid; Stains; Statistical Data Interpretation; Statistical Models; Surrogate Markers; Symptoms; T-Lymphocyte; Testing; Therapeutic; Training; Translational Research; Ursidae Family; Vaccine Design; Viral; Viral Pathogenesis; Virus; age difference; antibody-dependent cell cytotoxicity; base; biosafety level 3 facility; comorbidity; experimental study; gender difference; innate immune sensing; insight; intersectionality; male; neutralizing antibody; new therapeutic target; novel; novel marker; pandemic disease; racial difference; rational design; response; sample fixation; severe COVID-19; sex; single cell analysis; therapeutic evaluation; therapy development; vaccine candidate; vaccine development; vaccine evaluation; virology

Johns Hopkins has broad expertise in the science of human health, with viral immunity, pathogenesis, epidemiology, biostatistics, and surveillance emerging as integral components of the multidisciplinary research mounted at Johns Hopkins during the current pandemic. We propose development of a Serological Sciences Center of Excellence: the Johns Hopkins Excellence in Pathogenesis and Immunity Center for SARS-CoV-2 (JH-EPICS). The overarching goal of JH-EPICS is to distinguish immune responses that protect from those that cause pathology during infection. Under the Multiple PI leadership of Drs. Klein and Cox, the JH-EPICS Administrative Core will ensure resources and samples are available to systematically evaluate innate, T cell, and antibody responses to SARS-CoV-2 in peripheral blood mononuclear cells and serological samples from COVID-19 patients sampled longitudinally. JH-EPICS contains three interconnecting Research Projects (RPs). RP1 focuses on innate immune sensing and activation of the human inflammasome by SARS-CoV-2, with evaluation of how anti-SARS-CoV-2 antibodies modulate innate sensing. RP2 uses a novel flow-cytometry based platform that enables single cell analysis of traditional cell surface markers combined with intracellular staining for proteins involved in metabolic programming. Using this platform, we have identified distinct myeloid derived suppressor cells (MDSCs) and T cells abundant in COVID-19. RP1 will characterize these MDSCs, while RP2 will explore novel populations of T cells identified in COVID-19 patients. RP2 will also define novel biomarkers in order to predict severity of disease, track the course of disease, and define novel surrogate markers for testing therapeutic regimens. Together, RP1 and RP2 will identify novel therapeutic targets. In RP3, the magnitude, duration, and class switching of SARS-CoV-2-specific antibody isotypes as well as virus- specific neutralizing antibody responses will be analyzed and compared with non-neutralizing antibody functions, e.g., complement fixation and antibody-dependent cellular cytotoxicity, using a novel core set of serological assays. A centralized Virology Reagent Core will provide antigen for ELISAs, reagents to identify virus-specific immune cell populations, inactivated SARS-CoV-2 viruses, methods for quantifying SARS-CoV- 2, and access to biosafety level 3 facilities and training needed to perform any experiments involving live SARS-CoV-2. The Analysis Resource Core will provide statistical modeling and analysis to frame and test hypotheses about the mechanisms mediating the severity of COVID-19 as well as the intersectionality of sex, gender, age, and racial differences in immune mechanisms of COVID-19. In concert with the trans-network collaborations, this research will provide significant insights into pathologic immune responses to SARS-CoV-2, identification of novel therapeutic targets, and definition of immunity against SARS-CoV-2 infection. By uncovering the correlates of protective immunity, JH-EPICS research will further enhance vaccine design and evaluation of vaccine candidates.

约翰·霍普金斯大学在人类健康科学领域拥有广泛的专业知识，包括病毒免疫、发病机制、 流行病学、生物统计学和监测成为多学科研究不可或缺的组成部分 在当前的大流行期间安装在约翰·霍普金斯大学。我们建议发展血清学科学 卓越中心：约翰霍普金斯大学 SARS-CoV-2 发病机制和免疫卓越中心 （JH-EPICS）。 JH-EPICS 的首要目标是区分免疫反应，以防止这些反应 在感染期间引起病理。在 Drs 的多个 PI 领导下。克莱因和考克斯，JH-EPICS 管理核心将确保资源和样本可用于系统地评估先天、T 细胞、 外周血单核细胞和血清学样本中对 SARS-CoV-2 的抗体反应 对 COVID-19 患者进行纵向采样。 JH-EPICS 包含三个相互关联的研究项目 (RP)。 RP1 专注于先天免疫感应和 SARS-CoV-2 对人类炎症小体的激活， 评估抗 SARS-CoV-2 抗体如何调节先天感知。 RP2 使用新型流式细胞术 基于平台，能够对传统细胞表面标记物与细胞内标记物相结合进行单细胞分析 对参与代谢编程的蛋白质进行染色。使用这个平台，我们已经鉴定出不同的骨髓细胞 COVID-19 中富含衍生抑制细胞 (MDSC) 和 T 细胞。 RP1 将表征这些 MDSC， RP2 将探索在 COVID-19 患者中发现的新 T 细胞群。 RP2也将定义小说 生物标志物以预测疾病的严重程度、跟踪病程并定义新的替代物 用于测试治疗方案的标记。 RP1 和 RP2 将共同确定新的治疗靶点。在 RP3，SARS-CoV-2 特异性抗体同种型以及病毒的强度、持续时间和类别转换 将分析特异性中和抗体反应并与非中和抗体进行比较 使用一组新颖的核心功能，例如补体固定和抗体依赖性细胞毒性 血清学测定。集中式病毒学试剂核心将为 ELISA 提供抗原以及用于识别的试剂 病毒特异性免疫细胞群、灭活的 SARS-CoV-2 病毒、量化 SARS-CoV-的方法 2、获得生物安全 3 级设施和进行任何涉及活体实验所需的培训 SARS-CoV-2。分析资源核心将提供统计建模和分析来构建和测试 关于调节 COVID-19 严重程度以及性别交叉性的机制的假设， COVID-19 免疫机制中的性别、年龄和种族差异。与跨网络协同 合作，这项研究将为 SARS-CoV-2 的病理免疫反应提供重要的见解， 确定新的治疗靶点，以及针对 SARS-CoV-2 感染的免疫力的定义。经过 JH-EPICS 研究揭示了保护性免疫的相关性，将进一步加强疫苗设计和 候选疫苗的评估。