The role of the cAMP responsive protein AKAP9 in integrin mediated T cell recruitment to the kidney in acute kidney injury

cAMP 反应蛋白 AKAP9 在急性肾损伤中整合素介导的 T 细胞募集到肾脏中的作用

• 批准号: 227575761
• 负责人: Dr. Jan Herter
• 金额: --
• 依托单位: Department of Pathology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/227575761?language=en
• 关键词: role; cAMP; responsive; protein; AKAP9

Acute kidney injury (AKI) is characterized by an abrupt loss of kidney function. Despite technological advances, mortality rate of AKI has remained as high as 60% for decades. T-cells, specifically natural killer T-cells, were demonstrated to play critical roles in the pathophysiology of kidney injury as mice deficient in T-cells are protected from AKI. Leukocyte recruitment relies on the activation of ý2-integrins which interact with their counter-receptors to mediate cell arrest and consecutive infiltration of inflamed tissues.Integrin activation via G-protein coupled receptors (GPCR) is regulated by cAMP, an ubiquitous cellular second messenger that is involved in multiple signaling pathways. Even though cAMP was found to inhibit leukocyte integrin activation in response to chemokines, the molecular mechanism for this phenomenon remains elusive. An emerging concept is that A-kinase anchor proteins (AKAPs) serve to compartmentalize cAMP responses by targeting a subset of effector proteins to subcellular structures. In leukocytes, AKAP9 associates with the ý2-integrin leukocyte functioning antigen 1 (LFA-1) and inhibition of the cAMP effector protein kinase A results in increased LFA-1 activation.By using conditional knock-out mice deficient for AKAP9 in CD4+ and CD8+ T-cells this project aims to examine the importance of AKAP9 for cAMP dependent regulation of LFA-1. A comprehensive approach incorporating in vitro analysis of the signaling pathways leading to integrin activation and spatiotemporal distribution of key molecules as well as in vivo studies assessing the recruitment of T-cells to the inflamed vessel wall using intravital microscopy is deployed and the clinical importance of our hypothesis is tested in a murine model of acute kidney failure.

急性肾损伤(AKI)的特征是肾功能的突然丧失。尽管技术进步，AKI的死亡率几十年来一直保持在60%的高位。T细胞，特别是自然杀伤T细胞，被证明在肾脏损伤的病理生理学中发挥关键作用，因为T细胞缺陷的小鼠受到AKI的保护。白细胞的募集依赖于与其反向受体相互作用的整合素的激活，以介导细胞停滞和炎症组织的连续渗透。整合素的激活通过G蛋白偶联受体(GPCR)受cAMP调节，cAMP是一种普遍存在的细胞第二信使，参与多种信号通路。尽管cAMP被发现抑制趋化因子对白细胞整合素的激活，但这种现象的分子机制仍不清楚。一个新兴的概念是，A-激酶锚定蛋白(AKAP)通过靶向亚细胞结构的一部分效应蛋白来区分cAMP反应。在白细胞中，AKAP9与整合素白细胞功能抗原1(LFA-1)相关，抑制cAMP效应蛋白激酶A会导致LFA-1的激活增加。本项目旨在通过在CD4+和CD8+T细胞中缺乏AKAP9的条件性基因敲除小鼠来检验AKAP9在cAMP依赖的调节LFA-1中的重要性。我们采用了一种全面的方法，结合了导致整合素激活的信号通路的体外分析和关键分子的时空分布，以及使用活体显微镜评估T细胞到炎症血管壁的招募的体内研究，并在急性肾功能衰竭的小鼠模型中验证了我们假设的临床重要性。

项目成果

Integrin Regulation during Leukocyte Recruitment

• DOI: 10.4049/jimmunol.1203179
• 发表时间: 2013-05-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Herter, Jan;Zarbock, Alexander
• 通讯作者: Zarbock, Alexander

Adhesion Molecules Involved in Neutrophil Recruitment during Sepsis-Induced Acute Kidney Injury

• DOI: 10.1159/000358238
• 发表时间: 2014-01-01
• 期刊: JOURNAL OF INNATE IMMUNITY
• 影响因子: 5.3
• 作者: Herter, Jan M.;Rossaint, Jan;Zarbock, Alexander
• 通讯作者: Zarbock, Alexander

AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function.

• DOI: 10.1016/j.ajpath.2015.10.007
• 发表时间: 2016-02
• 期刊: The American journal of pathology
• 作者: Deepak Venkatesh;D. Mruk;J. Herter;X. Cullere;K. Chojnacka;C. Cheng;T. Mayadas