C-reactive protein in acute kidney injury

描述（由申请方提供）：急性肾损伤（阿基）-定义为肾脏排泄功能的快速且通常完全丧失-是多种临床环境中常见的危及生命的并发症，包括败血症、血容量不足、心脏手术和肾移植。每年在美国住院的所有人中有近2%患有阿基。他们的死亡率可高达80%，阿基幸存的患者住院时间更长，需要长期透析的可能性接近8%。在美国，阿基的财务成本是巨大的-估计每年为100亿美元。目前还没有特异性的治疗方法来预防阿基，加速其恢复，或消除其副作用，部分原因是阿基的发病机制尚未完全了解。人们认识到，无论其原因如何，阿基都伴随着炎症。然而，目前尚不清楚炎症的哪些成分是肾损伤的原因，哪些成分是肾损伤的后果，也不知道炎症是否调节损伤过程。通过寻求这些问题的答案，我们可以解决这一知识差距，并推动阿基领域向前发展。我们的长期目标是识别和绘制阿基中炎症的因果通路，并利用这些知识开发阿基的特异性疗法。本申请的目的是确定C-反应蛋白 (CRP)在阿基期间将白细胞导向炎性破坏途径。我们的中心假设是，在阿基期间，CRP以Fc R依赖性方式进行树突状细胞、中性粒细胞、单核细胞和巨噬细胞的协调作用，其阻止组织损伤并阻碍其修复。这一中心假设是基于在临床和体外发表的观察结果以及我们使用CRP转基因和CRP敲除小鼠生成的初步数据制定的，所有这些都表明CRP会加重阿基。我们研究的基本原理是，通过建立CRP因果关系，我们将把这种蛋白质从炎症生物标志物的地位提升为阿基的新治疗靶点，这是非常需要的。我们将通过追求4个具体目标来测试我们的中心假设。目的1是鉴定导致阿基的CRP反应性白细胞：假设CRP以加重阿基并阻碍肾脏修复过程的方式改变树突状细胞、中性粒细胞、单核细胞和巨噬细胞的作用。目的2是确定CRP如何在阿基中引起损伤性白细胞反应：假设CRP触发白细胞作用的改变取决于CRP与Fc受体的结合。目的3是确定损伤性CRP的来源：假设CRP在肝脏（而不是肾脏）中表达是加重损伤的原因。目的4是评估疗效 阿基中的CRP靶向：假设CRP的药理学降低将减轻阿基的严重程度。将通过使CRP转基因小鼠与缺乏特定白细胞群或Fc R的对应小鼠经受实验诱导的阿基来检验这些工作假设。将测试新型CRP降低药物的功效。该项目的成功将确定CRP如何启动，驱动和修改阿基，并揭示阿基的潜在新疗法。

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.