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

项目摘要/摘要 背景：败血症的全球负担集中在撒哈拉以南非洲(SSA)，那里流行着艾滋病毒， 广泛的病原体多样性和有限的危重护理能力挑战了对危及生命的有效管理 感染。在这种情况下，在尝试实施败血症治疗方案的情况下，在高收入国家开发的 国家(HIC)未能显示出好处，提供与当地相关的脓毒症病理生物学模型的数据是 少之又少。因为治疗反应可能部分地依赖于修改由 一系列病原体，对SSA脓毒症固有的生物异质性的不精确理解代表了一种 制定有效的管理战略的关键障碍。研究：这是研究的组成部分 该提案将利用NIAID和基金会资助的前瞻性队列研究的数据和生物样本 通过哥伦比亚大学和乌干达之间的合作，在乌干达进行了脓毒症的研究 病毒研究所(UVRI)。在这个框架内，我将建立新的临床分子败血症亚型 在乌干达使用临床、微生物和宿主生物标记物数据的潜在类别分析(目标1)； 通过将机器学习技术应用于全血来验证乌干达转录型脓毒症亚型 RNA测序数据(目标2)和；确定与重症相关的先天和细胞介导的免疫模式 艾滋病毒相关脓毒症的器官衰竭和死亡率(目标3)。候选人：如本K23奖项所述 我的职业目标是成为一名独立的临床和翻译研究员，专注于 资源有限环境中的败血症和感染相关危重疾病，目的是建立更精确的、 生物知情的临床管理策略，可在当地相关的临床试验中进行测试。我是 完全有资格承担这里提出的科学和培训目标，在过去的大部分时间里 十年致力于确定与以下疾病有关的新发感染的临床和分子流行病学特征 乌干达的重病和危重疾病。导师/环境：在Max博士的主要指导下 O‘Donnell是哥伦比亚大学R01资助的研究员，在SSA拥有15年的临床研究经验，我 我在哥伦比亚大学(Ian Lipkin博士、Jason Che博士)和UVRI组建了一个由共同导师和合作者组成的团队 (Barnabas Bakamutumaho博士)在传染病方面以患者为导向和翻译研究方面的专业知识 疾病和危重护理、全球健康、分子实验室方法以及高级生物统计学和 生物信息学。培训：在我的导师和合作者的指导下，我制定了一个严格的五年 职业发展计划，包括在以下方面的必要培训：临床研究设计、伦理和开展相关 到资源有限的环境(O‘Donnell博士、Bakamutumaho博士)、高通量RNA测序和生物标志物 计量(利普金博士)、高级生物统计学和生物信息学(切博士)和研究传播 和职业发展(所有导师)。完成拟议的培训和相关目标将有助于 作为一名独立的临床-翻译研究员和全球脓毒症研究的领导者，我的发展。

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.