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C-reactive protein in acute kidney injury

C反应蛋白在急性肾损伤中的作用

基本信息

批准号：
8693107
负责人：
ALEXANDER J SZALAI
金额：
$ 30.34万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8693107
关键词：
Acute Renal Failure with Renal Papillary Necrosis Address Adverse effects Albumins American Animal Model Anti-Inflammatory Agents Anti-inflammatory Biological Markers Biology Blood C-reactive protein Cardiac Surgery procedures Cell Adhesion Molecules Chronic Kidney Failure Clinic Clinical Complication Data Dendritic Cells Dendritic cell activation Development Dialysis procedure Donor person Drug Targeting Etiology Excretory function Fc Receptor Financial cost Goals Healthcare Systems Hepatic Hospitalization Human Hypovolemia In Vitro Individual Infiltration Inflammation Inflammatory Injury Injury to Kidney Intensive Care Units Kidney Kidney Transplantation Knockout Mice Knowledge Leukocytes Life Liver Long-Term Care Maps Mediating Modification Mus National Hospital Discharge Survey Neutrophil Infiltration Outcome Pathogenesis Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacotherapy Population Process Production Protein Binding Proteins Publishing Recovery Renal function Reperfusion Injury Reporting Research Role Sepsis Severities Source Syndrome Testing Therapeutic Intervention Time Tissues Toll-Like Receptor 5 Transgenic Mice Transgenic Organisms Transplant Recipients Transplantation United States Urine Work base cytokine effective therapy graft failure innovation kidney repair leukocyte activation macrophage monocyte mortality neutrophil new therapeutic target novel prevent protein expression public health relevance renal ischemia repaired response success therapeutic target

项目摘要

DESCRIPTION (provided by applicant):: Acute kidney injury (AKI) - defined by rapid and often complete loss of the kidney's excretory function - is a common life-threatening complication in diverse clinical settings including sepsis, hypovolemia, cardiac surgery, and kidney transplantation. Nearly 2% of all people hospitalized in the United States each year suffer from AKI. Their mortality rate can be as high as 80% and patients who survive AKI have longer hospitalizations and nearly an 8% chance of needing long-term dialysis. The financial cost of AKI in the United States is enormous - estimated to be $10 billion annually. There is no specific therapy to prevent AKI, to hasten its recovery, or to abrogate its side effects partly because the pathogenesis of AKI is not fully understood. It is recognized that whatever its cause, AKI is accompanied by inflammation. However, it is not known what components of inflammation are causes versus what components are consequences of kidney damage and it is not known if inflammation regulates the injury process. By seeking answers to these questions we can address this knowledge gap and drive the AKI field forward. Our long-term goal is to identify and map causal pathways of inflammation in AKI and harness this knowledge to develop specific therapies for AKI. The objective of the current application is to establish that C-reactive protein (CRP) steers leukocytes towards a pathway of inflammatory destruction during AKI. Our central hypothesis is that during AKI, CRP conducts the orchestrated actions of dendritic cells, neutrophils, monocytes, and macrophages in an Fc R- dependent fashion that worsens tissue injury and hampers its repair. This central hypothesis was formulated based on published observations made in the clinic and in vitro and preliminary data that we generated using CRP transgenic and CRP knockout mice, all indicating that CRP exacerbates AKI. The rationale for our research is that by establishing CRP causality we will elevate this protein from the status of biomarker of inflammation to new therapeutic target for AKI, which is sorely needed. We will test our central hypothesis by pursuing 4 specific aims. Aim 1 is to identify CRP-responsive leukocytes that contribute to AKI: The hypothesis being that CRP modifies dendritic cell, neutrophil, monocyte, and macrophage actions in ways that worsen AKI and hamper the kidney repair process. Aim 2 is to determine how CRP elicits injurious leukocyte responses in AKI: The hypothesis is that CRP triggered modification of leukocyte actions depends on CRP binding to Fc receptors. Aim 3 is to ascertain the source of injurious CRP: The hypothesis is that CRP expressed in the liver (not the kidney) is what exacerbates injury. Aim 4 is to assess the efficacy of CRP targeting in AKI: The hypothesis is that pharmacologic lowering of CRP will lessen AKI severity. These working hypotheses will be tested by subjecting CRP transgenic mice versus their counterparts lacking specific leukocyte populations or Fc Rs, to experimentally induced AKI. Efficacy of a novel CRP lowering drug will be tested. The project's success will establish how CRP initiates, drives, and modifies AKI and reveal a potential new therapy for AKI.

描述(由申请人提供)：急性肾损伤(AKI)-由肾脏排泄功能迅速且经常完全丧失-是各种临床环境中常见的危及生命的并发症，包括败血症、血容量减少、心脏手术和肾移植。每年在美国住院的人中，有近2%的人患有AKI。他们的死亡率可能高达80%，而存活下来的AKI患者住院时间更长，需要长期透析的可能性接近8%。在美国，AKI的财务成本是巨大的--估计每年高达100亿美元。目前尚无特效疗法来预防AKI、加速其恢复或消除其副作用，部分原因是AKI的发病机制尚不完全清楚。人们认识到，无论其原因是什么，AKI都伴随着炎症。然而，目前尚不清楚炎症的哪些成分是导致肾损害的原因，哪些成分是肾脏损害的后果，也不知道炎症是否调节了损伤过程。通过寻求这些问题的答案，我们可以解决这一知识差距，并推动AKI领域向前发展。我们的长期目标是确定和绘制AKI炎症的因果路径，并利用这一知识开发AKI的特定治疗方法。目前应用的目标是建立C反应蛋白 (CRP)在AKI过程中引导白细胞走向炎性破坏的途径。我们的中心假设是，在AKI期间，CRP以Fc-R依赖的方式引导树突状细胞、中性粒细胞、单核细胞和巨噬细胞的协调活动，从而加重组织损伤并阻碍其修复。这一中心假设是基于已发表的临床和体外观察以及我们使用CRP转基因和CRP基因敲除小鼠产生的初步数据提出的，所有这些数据都表明，CRP加剧了AKI。我们研究的基本原理是，通过建立CRP因果关系，我们将把这种蛋白从炎症的生物标记物的地位提升到AKI的新治疗靶点，这是迫切需要的。我们将通过追求4个具体目标来检验我们的中心假设。目的1是确定参与AKI的C反应蛋白反应性白细胞：假设C反应蛋白改变树突状细胞、中性粒细胞、单核细胞和巨噬细胞的活动，从而加重AKI并阻碍肾脏修复过程。目的2确定CRP如何在AKI中引起损伤性白细胞反应：假设CRP触发的白细胞活动的修饰依赖于CRP与Fc受体的结合。目的3是确定损伤C反应蛋白的来源：假设C反应蛋白在肝脏(而不是肾脏)的表达是加剧损伤的原因。目标4是评估疗效急性心肌梗死中的CRP靶向：假设药物降低CRP将减轻急性心肌梗死的严重程度。这些工作假说将通过让CRP转基因小鼠与缺乏特定白细胞群或Fc R的小鼠进行实验诱导的AKI来验证。一种新的降低CRP药物的疗效将得到测试。该项目的成功将确定CRP如何启动、驱动和修改AKI，并揭示一种潜在的AKI新疗法。