Temporal Transcriptomics in Hospitalized COVID-19 Patients from Disparately Impacted Ancestral Groups for Therapeutic Discovery

来自不同受影响祖先群体的住院 COVID-19 患者的时间转录组学用于治疗发现

• 批准号: 10661693
• 负责人: Douglas Jay Perkins
• 金额: $ 75.72万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661693
• 关键词: 2019-nCoV; Academic Medical Centers; Address; Affect; African; African American population; Age; Alaska Native; American Indians; Blood specimen; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; COVID-19 treatment; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Communicable Diseases; Country; Data; Development; Disease; Disease Progression; Enrollment; Equilibrium; FDA approved; Fostering; Foundations; Future; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genomic approach; Hispanic Populations; Hispanic ancestry; Hispanic-serving Institution; Hospitalization; Hospitals; Human; Immune Response Genes; Immune response; Immunoassay; Immunotherapy; Individual; Inflammation Mediators; Institutional Review Boards; Investigation; Knowledge; Laboratories; Life; Mediating; Methodology; Methods; Minority Groups; Modeling; Molecular; Monitor; Morbidity - disease rate; Navajo; New Mexico; Outcome; Outcome Study; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Play; Population; Population Sizes; Positioning Attribute; Prognosis; Research Personnel; Risk Assessment; Role; Severity of illness; Therapeutic; Time; Universities; Upper respiratory tract; Vaccines; Viral; Viral Load result; World Health Organization; biomarker identification; biomedical referral center; comorbidity; drug repurposing; experience; gene network; global health; hospitalization rates; improved; improved outcome; mRNA sequencing; mortality; multidisciplinary; new therapeutic target; novel; novel coronavirus; novel therapeutics; outcome disparities; pandemic disease; patient population; peripheral blood; recruit; response; severe COVID-19; small molecule; tertiary care; transcriptomics; translational impact; trauma centers; tribal lands

PROJECT SUMMARY SARS-CoV-2 is a novel coronavirus which causes COVID-19, a disease that has infected >46M people resulting in >1.2M deaths by 31 October 2020. The US has the highest global case count (>9.2M) and mortality (>230K) with recent record-setting daily cases and hospitalization rates across the country. This has been particularly true for New Mexico (NM) where cases and hospitalizations are surging again. It is now recognized that certain minority groups, i.e., African Americans, Hispanics, and American Indians/Alaska Natives (AI/AN), suffer disproportionally from COVID-19. NM has the highest proportion of Hispanic ancestry, and one of the largest AI/AN populations, with these two groups representing 47% and 26% of the cumulative cases, respectively. After adjusting for population size, the AI/AN group has 3.3-fold higher cumulative case rates, 7.9-fold higher hospitalizations, and 10.6-fold higher age-adjusted mortality rates. As the only academic medical center and Level 1 Trauma Center in the state, the University of New Mexico Hospital (UNMH) has played a principal role in caring for patients with COVID-19. UNMH is the primary tertiary care referral center for NM and surrounding regions, including the Navajo Nation and other tribal lands. As such, we are uniquely positioned to address important gaps-in-knowledge about the molecular basis of increased COVID-19 disease severity and mortality in disproportionally affected ancestral groups. In mid-February, the UNM Center for Global Health assembled a multidisciplinary group of investigators to address the challenges of COVID-19. As of 31 October, we have recruited and followed 167 hospitalized patients with COVID-19, offering an opportunity for rapid translational impact within the planned three-year study. The experimental strategy parallels our ongoing R01 studies in African children utilizing mRNA-Seq to identify novel therapeutic targets (PI: Perkins). State-of-the-art methodologies and modeling efforts in place in our laboratories will be applied to create solutions for improving outcomes in COVID-19 patients. This will be achieved by following non-severe and severe COVID-19 patients across hospitalization from different ancestral groups to successfully complete three specific aims: 1) determine the impact of SARS-CoV-2 viral load dynamics on disease severity, 2) identify gene expression networks that mediate disease severity, and 3) identify prioritized FDA-approved compounds that modulate gene networks associated with enhanced disease severity for use in future clinical trials. In a short time, we have generated extensive data on viral load dynamics and identified novel gene networks with target-compound matches. We present data showing that individuals of AI/AN descent have significantly higher and protracted viral loads in peripheral blood and more severe disease, despite comparable co-morbid factors with other groups. The proposed investigations have direct translational impact, particularly in disproportionately affected ancestral groups by defining the host immune response to SARS-CoV-2, identifying biomarkers for risk assessment, prognosis, and disease progression, and fostering drug repurposing to reduce disease severity and mortality.

项目摘要 SARS-COV-2是一种新型的冠状病毒，导致Covid-19，这种疾病感染了4600万人，导致4600万人 到2020年10月31日，在> 1.2m的死亡中。 全国近期创纪录的日常病例和住院率。这特别是 对于新墨西哥州（NM），病例和住院再次激增。现在认识到 少数群体，即非裔美国人，西班牙裔和美国印第安人/阿拉斯加本地人（AI/AN） 与Covid-19的不成比例。 NM是西班牙裔血统的最高比例，也是最大的 AI/A A A/A人群分别占累积病例的47％和26％。后 调整人口规模，AI/A组的累积病例率高3.3倍，高7.9倍 住院和年龄调整后的死亡率更高10.6倍。作为唯一的学术医疗中心， 新墨西哥大学医院（UNMH）在该州1级创伤中心发挥了主要作用 在照顾Covid-19患者中。 UNMH是NM和周围的主要三级护理推荐中心 包括纳瓦霍国家和其他部落土地在内的地区。因此，我们有独特的位置来解决 关于增长的Covid-19疾病严重程度和死亡率的分子基础的重要差距 在不成比例的受影响的祖先群体中。 2月中旬，全球卫生中心集会 多学科研究人员解决了Covid-19的挑战。截至10月31日，我们有 招募并跟随167例Covid-19患者，为快速翻译提供了机会 在计划的三年研究中的影响。实验策略与我们正在进行的R01研究相似 使用mRNA-SEQ鉴定新的治疗靶标（PI：Perkins）的非洲儿童。最先进的 我们的实验室中将采用方法和建模工​​作来创建用于改进的解决方案 COVID-19患者的结果。这将通过跟随非严重和严重的Covid-19患者来实现 从不同祖先群体的住院治疗，成功完成了三个具体目标：1）确定 SARS-COV-2病毒负荷动力学对疾病严重程度的影响，2）确定基因表达网络 介导疾病的严重程度，3）确定调节基因网络的优先考虑的FDA批准的化合物 与增强的疾病严重程度相关，以在以后的临床试验中使用。在短时间内，我们产生了 有关病毒载荷动力学的广泛数据，并鉴定出具有目标化合物匹配的新型基因网络。我们 目前的数据表明，AI/A An下降的个体在 尽管与其他群体相当的合并因素可比，但周围血液和更严重的疾病。这 拟议的调查具有直接的翻译影响，尤其是在受影响不成比例的祖先方面 通过定义宿主对SARS-COV-2的免疫反应，识别生物标志物以进行风险评估， 预后，疾病进展，并促进药物重新利用以降低疾病的严重程度和死亡率。