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

项目总结/摘要 背景：脓毒症的全球负担集中在撒哈拉以南非洲（SSA），那里流行艾滋病毒， 广泛的病原体多样性和有限的重症监护能力挑战了对危及生命的 感染.在这种情况下，如果试图实施在高收入国家开发的脓毒症治疗方案， 尽管高收入国家（HIC）未能显示出获益，但为脓毒症病理生物学的当地相关模型提供信息的数据 稀少。由于治疗反应可能部分取决于改变由免疫刺激引起的复杂宿主反应， 病原体的阵列，不精确的理解固有的生物异质性，脓毒症在SSA代表了一个 制定有效管理战略的关键障碍。研究：本研究的组成部分 一项提案将利用来自NIAID和基金会资助的前瞻性队列研究的数据和生物样本 通过哥伦比亚大学和乌干达之间的既定合作， 病毒研究所（UVRI）。在这个框架内，我将建立新的临床分子脓毒症亚型 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（目标1）; 通过将机器学习技术应用于全血来验证乌干达的转录组败血症亚型 RNA测序数据（目标2）;确定与严重急性淋巴细胞白血病相关的先天和细胞介导的免疫谱 HIV相关脓毒症的器官衰竭和死亡率（目的3）。候选人：如K23奖所述 我的职业目标是成为一名独立的临床和翻译研究者，专注于 脓毒症和感染相关的危重病在资源有限的环境中，目标是建立更精确， 生物学上知情的临床管理策略，可以在当地相关的临床试验中进行测试。我是 有资格承担这里提出的科学和培训目标，过去花了很多时间 十年来致力于表征与艾滋病相关的新出现的感染的临床和分子流行病学 严重和危急的疾病。导师/环境：在Max博士的主要指导下 奥唐纳是哥伦比亚R 01资助的研究者，在SSA有超过15年的临床研究经验， 我在哥伦比亚大学（Ian Lipkin博士，Jason Che博士）和UVRI组建了一个共同导师和合作者团队 (Dr. Barnabas Bakamutumaho），在感染性疾病的患者导向和转化研究方面拥有专业知识 疾病和重症监护，全球健康，分子实验室方法，先进的生物统计学和 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计划， 职业发展计划，包括临床研究设计、伦理学和相关行为方面的必要培训 资源有限的环境（奥唐纳博士，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），以及研究传播 专业发展（所有导师）。完成拟议的培训和相关目标将有助于 我作为一个独立的临床转化研究者和全球脓毒症研究的领导者的发展。

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.