Impact of Red Blood Cell (RBC)-Derived DAMPs on Host Immune Response in Pediatric Sepsis

项目摘要 该提案包括一个4年计划，以准备肯尼思E。雷米，医学博士，MHSc。作为一个独立 研究血浆血红素代谢失调对宿主改变的影响的医生科学家 免疫力和开发针对这一问题的机械疗法。雷米博士之前在国家实验室的工作 卫生研究所和目前在华盛顿大学作为这一建议的基础。华盛顿 大学医学院是雷米博士发展他的研究平台的典范。 血液学免疫学，因为NIH资助的研究有着悠久的历史和广泛的资源 available.此外，各部门之间也存在显著的相互干扰（雷米博士的导师在两个不同的 部门）和其他机构，包括美国国立卫生研究院，哈佛大学和哥伦比亚大学（博士。 雷米提议的顾问小组）。 博士雷米的近期目标是实现这一建议中概述的目标。脓毒症是一种侵袭性传染病 与失调的全身性炎症相关，每年全球有超过400万人死亡。 缺乏特异性靶向治疗。其中许多患者（约50%）接受红细胞（RBC）输注 作为支持性治疗最近的证据表明，红细胞输注可能会进一步破坏患者的免疫功能， 导致更坏的结果。这种破坏可能与从细胞中释放游离血红素有因果关系。 红细胞输注，通过改变宿主免疫表型的演变来应对感染。该项目将重点 关于儿科败血症，有以下三个具体目标： 目的1：确定脓毒症期间输注红细胞对血浆中血红素加工的影响。 目的2：探讨血浆血红素对单核细胞免疫表型的影响。 目的3：阐明血浆血红素对Toll样受体4（TLR 4）和HO-1的作用。 单核细胞信号传导。 从成功实现这些目标中获得的知识将有助于确定影响和临床 红细胞输注对脓毒症患者血浆血红素代谢和免疫功能的影响， 一般来说，在其他严重疾病中。这些知识是至关重要的，以便雷米博士的实验室可以翻译这些 发展可能改善脓毒症结局的机制疗法。

PROJECT SUMMARY This proposal comprises a 4-year plan to prepare Kenneth E. Remy, MD, MHSc. for independence as a physician-scientist studying the influence of dysregulated plasma heme metabolism upon alterations to host immunity and to develop mechanistic therapies for this problem. Dr. Remy’s previous work at the National Institutes of Health and currently at Washington University serve as the basis for this proposal. Washington University School of Medicine is an exemplary location for Dr. Remy to develop his research platform in hematology-immunology, as there is a longstanding history of NIH funded research and breadth of resources available. Additionally, there is significant crosstalk among departments (Dr. Remy’s mentors across two different departments) and with other institutions including the NIH, Harvard University, and Columbia University (Dr. Remy’s proposed advisory panel). Dr. Remy’s immediate goal is to fulfill the aims outlined in this proposal. Sepsis is an invasive infectious disease associated with dysregulated systemic inflammation and more than 4 million deaths worldwide per annum. Specific targeted therapies are lacking. Many of these patients (~50%) receive a red blood cell (RBC) transfusion as supportive therapy. Recent evidence indicates that RBC transfusions may further disrupt a patient’s immune system and lead to worse outcomes. This disruption may be causally linked to release of free heme from the RBC transfusion, by altering evolution of host immune phenotype in response to infection. This project will focus on pediatric sepsis with the following three specific aims:  Aim 1: Determine the effect of RBC transfusion during sepsis on heme processing in plasma.  Aim 2: Characterize the effect of plasma heme on monocyte immune phenotype.  Aim 3: Elucidate the effect of plasma heme on toll-like receptor 4 (TLR4) - and HO-1-based monocyte signaling. The knowledge gained from successfully achieving these aims will help define the impacts and clinical consequences of RBC transfusion on plasma heme metabolism and immune function in sepsis and, more generally, in other critical illnesses. This knowledge is crucial so that Dr. Remy’s laboratory can translate these to development of mechanistic therapies that may improve sepsis outcomes.