Subtyping sepsis in Uganda using clinical, pathogen, and host response profiling

使用临床、病原体和宿主反应分析对乌干达脓毒症进行分型

• 批准号: 10560608
• 负责人: Matthew John Cummings
• 金额: $ 19.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-02 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560608
• 关键词: Address; Adult; Affect; Africa South of the Sahara; Bioinformatics; Biological; Biological Markers; Biometry; Blood specimen; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cessation of life; Clinical; Clinical Data; Clinical Investigator; Clinical Management; Clinical Research; Clinical Trials; Clinical Trials Design; Collaborations; Communicable Diseases; Complement; Complex; Country; Critical Care; Critical Illness; Data; Derivation procedure; Development; Development Plans; Diagnosis; Environment; Epidemic; Epidemiology; Ethics; Fibrinolysis; Foundations; Funding; Genomics; Goals; HIV; Health system; High-Throughput RNA Sequencing; Hospitals; Immune; Immune System Diseases; Immune response; Immunologist; Immunology; Income; Infection; Inflammatory; Knowledge; Laboratories; Life; Machine Learning; Malnutrition; Measurement; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Modeling; Molecular; Molecular Epidemiology; National Institute of Allergy and Infectious Disease; Natural Killer Cells; Organ failure; Outcome; Pathway interactions; Patient-Focused Outcomes; Phenotype; Pilot Projects; Prospective, cohort study; Qualifying; RNA; RNA analysis; Research; Research Design; Research Institute; Research Personnel; Resolution; Resource-limited setting; Sampling; Scientist; Sepsis; T-Lymphocyte; Techniques; Testing; Training; Translational Research; Treatment Efficacy; Treatment Protocols; Uganda; Universities; Virus; Whole Blood; biological heterogeneity; biomarker driven; career; career development; cell type; clinical epidemiology; clinical heterogeneity; clinical translation; clinically relevant; cohort; comorbidity; cytokine; endothelial dysfunction; exhaustion; experience; functional genomics; genetic signature; global health; high risk; immune activation; immune modulating agents; immunomodulatory therapies; improved; mortality; novel; pathogen; pathogen genomics; patient oriented; patient oriented research; patient stratification; prospective; research data dissemination; response; septic; septic patients; tool; transcriptome; transcriptome sequencing; transcriptomics; translational scientist; treatment response; treatment strategy; unsupervised learning

PROJECT SUMMARY / ABSTRACT Background: The global burden of sepsis is concentrated in sub-Saharan Africa (SSA), where epidemic HIV, broad pathogen diversity, and limited critical care capacity challenge effective management of life-threatening infections. In this context, where attempts to implement sepsis treatment protocols developed in high-income countries (HICs) have failed to show benefit, data informing locally-relevant models of sepsis pathobiology are scarce. As treatment responses likely depend, in part, on modifying complex host responses incited by an array of pathogens, imprecise understanding of biological heterogeneity inherent to sepsis in SSA represents a crucial barrier to development of effective management strategies. Research: The research component of this proposal will utilize data and biological samples from NIAID- and foundation-funded prospective cohort studies of sepsis in Uganda conducted through an established collaboration between Columbia University and Uganda Virus Research Institute (UVRI). Within this framework, I will establish novel clinico-molecular sepsis subtypes in Uganda using latent class analysis of clinical, microbiological, and host biomarker data (Aim 1); derive and validate transcriptomic sepsis subtypes in Uganda by applying machine learning techniques to whole-blood RNA sequencing data (Aim 2) and; determine innate and cell-mediated immune profiles associated with severe organ failure and mortality in HIV-associated sepsis (Aim 3). Candidate: As outlined in this K23 Award application, my career objective is to become an independent clinical and translational investigator focused on sepsis and infection-related critical illness in resource-limited settings, with the goal to establish more precise, biologically-informed clinical management strategies that can be tested in locally-relevant clinical trials. I am well-qualified to undertake the scientific and training Aims proposed here, having spent much of the past decade working to characterize the clinical and molecular epidemiology of emerging infections associated with severe and critical illness in Uganda. Mentors/Environment: Under the primary mentorship of Dr. Max O’Donnell, an R01-funded investigator at Columbia with >15 years of clinical research experience in SSA, I have assembled a team of co-mentors and collaborators at Columbia (Dr. Ian Lipkin, Dr. Jason Che) and UVRI (Dr. Barnabas Bakamutumaho) with expertise in patient-oriented and translational research in infectious diseases and critical care, global health, molecular laboratory methods, and advanced biostatistics and bioinformatics. Training: With guidance from my mentors and collaborators, I have crafted a rigorous five-year career development plan that includes necessary training in: clinical study design, ethics, and conduct relevant to resource-limited settings (Drs. O’Donnell, Bakamutumaho), high-throughput RNA sequencing and biomarker measurement (Dr. Lipkin), advanced biostatistics and bioinformatics (Dr. Che), and research dissemination and professional development (all mentors). Completion of the proposed training and related Aims will facilitate my development as an independent clinical-translational investigator and leader in global sepsis research.

项目摘要 /摘要 背景：败血症的全球燃烧集中在撒哈拉以南非洲（SSA）中，流行艾滋病毒， 广泛的病原体多样性和有限的重症监护能力挑战有效地管理生命 感染。在这种情况下，尝试实施高收入中开发的败血症治疗方案 国家（HIC）未能表现出好处，与本地有关脓毒症病理生物学模型的数据是 稀缺。由于治疗反应可能部分取决于修改由 病原体阵列，侵入对SSA中败血症生物异质性的理解代表 制定有效管理策略的关键障碍。研究：研究部分 提案将利用来自NIAID和基金会资助的前瞻性队列研究的数据和生物样品 乌干达的败血症的作品是通过哥伦比亚大学和乌干达建立的合作进行的 病毒研究所（UVRI）。在此框架内，我将建立新型的临床败血症亚型 在乌干达使用临床，微生物和宿主生物标志物数据的潜在类别分析（AIM 1）；衍生和 通过将机器学习技术应用于全血，验证乌干达的转录组败血症亚型 RNA测序数据（AIM 2）和；确定与重度相关的先天和细胞介导的免疫特征 艾滋病毒相关败血症的器官衰竭和死亡率（AIM 3）。候选人：正如该K23奖中概述的 应用，我的职业目标是成为专注于的独立临床和翻译的研究者 在资源有限的环境中，败血症和与感染有关的危害疾病，目的是建立更精确的， 可以在本地临床试验中测试的生物知识临床管理策略。我是 合格的是在这里提出的科学和培训目标，过去大部分时间 十年来，旨在表征与 乌干达的严重疾病。导师/环境：Max博士的主要心态 O'Donnell是哥伦比亚R01资助的研究员，在SSA中拥有> 15年的临床研究经验，我 已经在哥伦比亚（Ian Lipkin博士，Jason Che博士）和Uvri组成了一支联合和合作者团队 （Barnabas Bakamutumaho博士）与以患者为导向和翻译的感染性研究专家 疾病和重症监护，全球健康，分子实验室方法以及先进的生物统计学和 生物信息学。培训：在导师和合作者的指导下，我精心制作了一个严格的五年 职业发展计划，其中包括：临床研究设计，道德和行为相关的必要培训 到资源有限的设置（O'Donnell博士，Bakamutumaho），高通量RNA测序和生物标志物 测量（Lipkin博士），高级生物统计学和生物信息学（CHE博士）和研究传播 和专业发展（所有导师）。拟议的培训和相关目标的完成将有助于 我作为全球败血症研究的独立临床翻译研究者和领导者的发展。