SEPSIS-INDUCED RED CELL DYSFUNCTION (SIRD)

脓毒症引起的红细胞功能障碍 (SIRD)

基本信息

批准号：
9069918
负责人：
ALLAN DOCTOR
金额：
$ 78.8万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9069918
关键词：
Adhesions Affinity Antioxidants Binding Biochemical Biochemistry Biological Assay Biology Blood Blood Vessels Blood flow Cardiac Output Cell Adhesion Cell Aggregation Cell Energetics Cell physiology Characteristics Child Childhood Chronic Clinical Data Comorbidity Coupling Critical Care Cues Cysteine Defect Development Diabetes Mellitus Dorsal Elements Endothelium Energy Metabolism Erythrocytes Evaluation Evolution Free Radicals Functional disorder Glucose Goals Health Heme Hemoglobin Incubated Inflammation Injury Kidney Failure Link Lipids Lung Medicine Membrane Membrane Proteins Metabolism Modeling Modification Multiple Organ Failure National Institute of Child Health and Human Development Network Infrastructure Nitric Oxide Nude Mice Organ Organ failure Outcome Oxidants Oxidation-Reduction Perfusion Pharmaceutical Chemistry Phenotype Physiological Process Production Purines Reactive Oxygen Species Recruitment Activity Regional Blood Flow Reporter Research Respiration Rheology Role Sepsis Sepsis Syndrome Signal Transduction Stress Structure Study Subject Sulfhydryl Compounds Superoxide Dismutase System Testing Tissues Vascular Diseases Vascular System base biophysical analysis cell injury cohort genetic regulatory protein in vivo Model intravital imaging intravital microscopy mimetics novel novel therapeutics optical imaging septic skeletal small molecule targeted treatment translational approach

项目摘要

DESCRIPTION (provided by applicant): The goals of this project are to: (1) fully characterize SIRD as a distinct form of organ failure impairing O2 delivery in sepsis, (2) elucidate SIRD's role in multiple organ failure (MOF) progression, and (3) evaluate a mechanism-based therapy targeted to SIRD pathobiology. In sepsis, a number of RBC defects have been (individually) described: altered O2 affinity, membrane deformability, RBC aggregation and adhesion, as well as dysregulated RBC-based nitric oxide (NO) processing. We suggest that these defects comprise a unique class of organ failure (which we term SiRD) that disables transport of O2 from lungs to tissue. Based upon our preliminary findings, we propose the novel hypothesis that in sepsis, energetic support of RBC antioxidant systems fails, with SiRD arising consequent to unquenched reactive oxygen species (ROS) generated in the course of hemoglobin O2 binding/release. As such, by critically impairing O2 delivery (by limiting both delivery of RBCs to tissue [e.g. flow] and release of O2 from delivered RBCs), SiRD exacerbates dysoxia and MOF progression. We propose a mechanistic 'reverse translational' approach to test this hypothesis in a comprehensively phenotyped cohort of children with severe sepsis (enabling us to study subjects lacking comorbidities which also impair RBC function, e.g. diabetes, renal failure, etc.). We will study children in the "Inflammation Phenotypes in Pediatric Sepsis Induced Multiple Organ Failure" (PHENOMS Trial [GM108618], which will be conducted by the NICHD Collaborative Pediatric Critical Care Research Network [CPCCRN]). This will enable us to leverage the established CPCCRN infrastructure and the detailed phenotype and outcome evaluation of the PHENOMS cohort so that we may link SiRD to progression of sepsis syndromes, MOF evolution, and to outcome. We will structure our approach by pursuing the following Specific Aims: SA1. Define sepsis-induced biochemical alterations to RBCs that influence O2 delivery. PHENOMS subjects' RBCs will be studied in ex vivo assay platforms, organ bioassays and in vivo models to quantitate defects in (and efficacy of SOD mimetics in restoring): O2 binding/delivery as well as control of vascular tone and blood flow. SA2 Define sepsis-induced biophysical alterations to RBCs that influence O2 delivery. As above, subjects' RBCs will be studied employing state of the art biophysical analysis (for membrane deformability, RBC aggregation and endothelial adhesion) and intravital microscopy to quantitate defects in (and efficacy of SOD mimetics in restoring): RBC transit through vascular channels and adhesion to activated endothelium. SA3 Characterize sepsis-induced alterations in RBC energy metabolism, antioxidant systems and oxidative injury. Study subjects' RBCs will be subjected to controlled oxidative loading to quantitate the dynamic range in (and efficacy of SOD mimetics in restoring): glycolytic flux (1H NMR analysis of lactate isotopomers), redox poise in antioxidant systems, and (c) oxidative injury to membrane and proteins.

描述（由申请人提供）：该项目的目标是：（1）完全将SIRD描述为败血症中O2递送的一种独特的器官衰竭形式，（2）阐明Sird的角色在多器官衰竭（MOF）进展中，（3）评估针对SIRD病理生物学的基于机制的治疗。在败血症中，已经描述了许多RBC缺陷：O2亲和力改变，膜变形性，RBC聚集和粘附以及基于RBC的一氧化氮（NO）处理失调。我们建议这些缺陷包括一类独特的器官衰竭（我们称为SIRD），该衰竭禁用O2从肺部传输到组织。基于我们的初步发现，我们提出了一个新的假设，即在败血症中，RBC抗氧化剂系统的能量支持失败，导致血红蛋白O2结合/释放过程中产生的无抑制活性活性氧（ROS）产生。因此，通过严重损害O2的交付（通过将RBC的交付限制为组织[例如流量]和O2从传递的RBC中释放），SIRD加剧DySoxia和MOF进展。我们提出了一种机械性的“反向翻译”方法来检验这一假设，该假设是严重败血症的儿童的全面表型（使我们能够研究缺乏合并症的受试者，这些合并症也损害了RBC功能，例如糖尿病，肾衰竭等）。我们将研究“小儿脓毒症的炎症表型会诱导多器官衰竭”（现象试验[GM108618]，这将由NICHD协作性儿科重症监护研究网络[CPCCRN]进行。这将使我们能够利用已建立的CPCCRN基础设施以及对现象队列的详细表型和结果评估，以便我们可以将SIRD与脓毒症综合征的进展，MOF进化和结果联系起来。我们将通过追求以下特定目标来构建我们的方法：SA1。定义败血症诱导的生化改变对影响O2递送的RBC。现象受试者的RBC将在离体测定平台，器官生物测定和体内模型中进行研究，以定量缺陷（SOD Mimetics在恢复中的功效）：O2结合/递送以及血管张力和血流的控制。 SA2定义了败血症诱导的生物物理改变对影响O2递送的RBC。 As above, subjects' RBCs will be studied employing state of the art biophysical analysis (for membrane deformability, RBC aggregation and endothelial adhesion) and intravital microscopy to quantitate defects in (and efficacy of SOD mimetics in restoring): RBC transit through vascular channels and adhesion to activated endothelium. SA3表征了败血症诱导的RBC能量代谢，抗氧化剂系统和氧化损伤的改变。研究对象的RBC将受到控制的氧化载荷，以量化（SOD MIMETICS在恢复中的动态范围）：糖酵解通量（乳酸同位素同位素剂的1H NMR分析），氧化还原系统中的氧化还原系统中的氧化还原溶液，以及（C）氧化性受损对膜素和蛋白质蛋白质和蛋白质。