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Role of CC chemokine signaling in hyperglycemic renal artery stenosis

CC趋化因子信号在高血糖肾动脉狭窄中的作用

基本信息

批准号：
9215631
负责人：
JOSEPH PETER GRANDE
金额：
$ 47.39万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215631
关键词：
Address Bilateral Bone Marrow Bone Marrow Transplantation CCL2 gene CD8-Positive T-Lymphocytes Cells Chronic Chronic Kidney Failure Clip Contralateral Development Diabetes Mellitus Disease Disease Progression Disease model Event Family Foundations Generations Goals Human Hyperglycemia Hyperlipidemia Hypertension Inflammation Inflammatory Injury Intervention Kidney Kidney Diseases Kidney Failure Knockout Mice Lesion Leukocytes Marrow Mediating Metabolic syndrome Modeling Morbidity - disease rate Mus Myocardial Infarction Obesity Outcome Patients Phenotype Play Process Renal Artery Stenosis Renovascular Hypertension Research Risk Factors Role Secondary to Signal Pathway Signal Transduction Stroke Testing Therapeutic Intervention Tissues United States beta-Chemokines chemokine cytokine db/db mouse kidney vascular structure macrophage member monocyte chemoattractant protein 1 receptor mortality mouse model novel prevent programs public health relevance reconstitution targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Optimal management of patients with renovascular hypertension (RVH) due to atherosclerotic renal artery stenosis (RAS) is a matter of considerable controversy. Our long-term goal is to identify signaling pathways responsible for the development of ischemic injury in the stenotic kidney and hypertensive injury in the contralateral kidney in the 2-kidney, 1-clip model of RVH. Our recent studies have underscored a critical role for MCP-1 (CCL2) and other members of the CC chemokine family in the development of chronic renal damage in murine RVH. CC chemokine expression plays a critical role in the progression of renal disease in patients with metabolic syndrome and diabetes (MetS-D), but less is known about their role in renovascular disease (RVD). Most studies have focused on chemokine generation by circulating inflammatory cells and tissue macrophages, although parenchymal cells can produce CC chemokines and thereby contribute to injury. The next logical step in our ongoing studies is to elucidate a critical role for CC chemokine signaling by renal parenchymal cells and infiltrating macrophages and other inflammatory cells in the progression of RVD and how this process is modulated by the presence of MetS-D. The central hypothesis underlying our ongoing studies is that CC chemokine signaling directs early events in macrophage influx and polarization, leading to chronic injury, and that chemokine generation by parenchymal cells may contribute to/amplify this process. Furthermore, macrophages play an important role in the development of chronic renal damage in the contralateral kidney, a process that depends on the presence of MetS-D, as suggested by our preliminary studies. Our aims are to 1) test the hypothesis that CC chemokines play a critical role in mediating the development and progression of bilateral chronic renal injury in mice with MetS-D and RVH; 2) test the hypothesis that progression of CKD in mice with MetS-D and RVH requires interaction of CC chemokine signaling through bone marrow derived macrophages and parenchymal cells; and 3) test the hypothesis that M1 polarization is necessary for initiation and progression of renal disease in MetS-D mice with RVH. The proposed studies will provide an essential foundation towards understanding a mechanistic role for macrophage polarization and CC chemokine generation in the development of chronic renal lesions in a novel mouse model of RVH with MetS-D.

描述（由申请人提供）：动脉粥样硬化性肾动脉狭窄（RAS）导致的肾血管性高血压（RVH）患者的最佳管理是一个相当有争议的问题。我们的长期目标是在RVH的2肾1夹模型中确定负责狭窄肾中缺血性损伤和对侧肾中高血压损伤发展的信号通路。我们最近的研究强调了MCP-1（CCL 2）和CC趋化因子家族的其他成员在小鼠RVH慢性肾损伤的发展中的关键作用。CC趋化因子表达在代谢综合征和糖尿病（MetS-D）患者的肾脏疾病进展中起着关键作用，但对其在肾血管疾病（RVD）中的作用知之甚少。大多数研究都集中在循环炎性细胞和组织巨噬细胞产生趋化因子，虽然实质细胞可以产生CC趋化因子，从而有助于损伤。我们正在进行的研究的下一个逻辑步骤是阐明CC趋化因子信号传导的关键作用肾实质细胞和浸润性巨噬细胞和其他炎性细胞在RVD进展中的作用，以及MetS-D的存在如何调节该过程。我们正在进行的研究的核心假设是CC趋化因子信号传导指导巨噬细胞流入和极化的早期事件，导致慢性损伤，并且实质细胞产生的趋化因子可能有助于/放大这一过程。此外，巨噬细胞在对侧肾的慢性肾损伤的发展中起重要作用，这一过程取决于MetS-D的存在，正如我们的初步研究所表明的那样。我们的目的是1）检验CC趋化因子在MetS-D和RVH小鼠中介导双侧慢性肾损伤的发生和进展中起关键作用的假设; 2）检验MetS-D和RVH小鼠中CKD的进展需要CC趋化因子信号通过骨髓源性巨噬细胞和实质细胞的相互作用的假设;以及3）检验M1极化对于患有RVH的MetS-D小鼠中的肾病的开始和进展是必需的这一假设。拟议的研究将提供一个重要的基础，了解机制的作用，巨噬细胞极化和CC趋化因子的产生在慢性肾脏病变的发展，在一个新的小鼠模型的RVH与MetS-D。