CHEMOKINE THERAPEUTIC TARGETS FOR KIDNEY DISEASE

肾脏疾病的趋化因子治疗靶点

• 批准号: 6628570
• 负责人: Vicki Rubin Kelley
• 金额: $ 24.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628570
• 关键词: Lentivirus; T lymphocyte; apoptosis; cytokine receptors; disease /disorder model; gene therapy; laboratory mouse; leukocyte activation /transformation; lung disorder; macrophage; monocyte chemoattractant protein 1; nephritis; nonhuman therapy evaluation; salivary disorder; skin disorder; systemic lupus erythematosus; transfection

DESCRIPTION:An influx of leukocytes is common to progressive kidney diseases. Targeting specific molecules responsible for recruitment of leukocytes into the kidney provides a therapeutic strategy for halting tissue progressive damage. Monocyte chemoattractant protein-1(MCP-1) belongs to a family of "chemokines" which attract leukocytes to tissues targeted for inflammation. MCP-l is abundantly expressed by renal parenchymal cells during progressive renal injury. Blockade of MCP-l reduces the influx of activated macrophages, thereby sparing the tubules from macrophage mediated apoptotic destruction in acute nephrotoxic serum nephritis. The MRL-Faslpr model is appealing to identify therapeutic targets for progressive kidney disease since renal destruction is spontaneous, steadily progressive, predictable, fatal and shares features with human illnesses. Kidney disease in the MRL-Faslpr model is complex and consists of glomerular, tubular and peri-vascular damage, accompanied by an robust influx of macrophages and lymphocytes. MCP-1 is vigorously expressed in the MRL-Faslpr kidney prior to injury, and increases with advancing disease. We have constructed an MRL-Faslpr strain genetically deficient in MCP-1 and determined that mice lacking MCP-l live far longer than the wild-type strain. Using genetic approaches, we propose to test the hypothesis that MCP-1 is a therapeutic target for progressive autoimmune kidney disease. We propose to: 1) determine whether MCP-1 is required for autoimmune renal disease. We will establish whether MCP-1(-/-) deficient MRL-Faslpr mice are protected from kidney disease, and determine whether protection is exclusive to the kidney, or is systemic. 2) determine whether delivery of MCP-1 into the kidney amplifies or incites progressive renal disease. Using a retroviral gene transfer approach that provides for sustained delivery of MCP-l to a discrete area of the kidney, we propose to determine the impact of local MCP-1 expression on renal pathology, and to investigate whether MCP-1 restores pathology within a discrete area in MCP-l deficient MRL-Faslpr kidneys. We will establish whether MCP-1 is required for autoimmune nephritis in the NZM241O strain. 3) establish whether delivery of MCP-1 receptor antagonist (MCP-1ra) into the MRLFaslpr kidney prevents injury. We propose to: deliver MCP-lra to a discrete segment of the kidney using an ex vivo retroviral gene transfer and throughout the kidney using a lentiviral vector in vivo. We will establish the crucial period for MCP- 1 r blockade via a tetracycline transactivator system to switch delivery of MCP- ira "on and off" at stages during the progression of nephritis. 4) establish the role of chemokines that share the CCR2 with MCP-1 in MRL-Faslpr mice. We propose to compare renal disease in MRL-Faslprstrains deficient in CCR2 and MCP-l to establish whether other MCPs are potential_therapeutic targets for kidney disease.

描述：白细胞涌入是进行性肾脏疾病常见的。 靶向负责将白细胞募集到该的特定分子 肾脏提供了制止组织进行性损害的治疗策略。 单核细胞趋化剂蛋白1（MCP-1）属于“趋化因子”家族 吸引白细胞到针对炎症的组织。 MCP-L是 在进行性肾脏期间由肾实质细胞大量表达 受伤。 MCP-L的封锁减少了活化巨噬细胞的涌入 在急性中保留巨噬细胞介导的凋亡破坏中的小管 肾毒性血清肾炎。 MRL-FASLPR模型吸引了确定 由于肾脏破坏是进行进行性肾脏疾病的治疗靶标的 自发，稳定进步，可预测，致命，并与之共享特征 人类疾病。 MRL-FASLPR模型中的肾脏疾病很复杂，并且包括 肾小球，管状和血管周围损伤，并伴有坚固的 巨噬细胞和淋巴细胞的涌入。 MCP-1在 受伤前MRL-FASLPR肾脏，并随着疾病的发展而增加。我们 在MCP-1和 确定缺乏MCP-L的小鼠的寿命比野生型菌株更长。 使用遗传方法，我们建议测试MCP-1是一个的假设 进行性自身免疫性肾脏疾病的治疗靶标。我们建议：1） 确定自身免疫性肾脏疾病是否需要MCP-1。我们将 确定MCP-1（ - / - ）是否保护MRL-FASLPR小鼠免受保护 肾脏疾病，并确定保护是否是肾脏的独有的，还是 是系统的。 2）确定将MCP-1输送到肾脏放大中是否会产生 或促进进行性肾脏疾病。使用逆转录病毒基因转移方法 这规定了将MCP-L持续交付到肾脏的离散区域， 我们建议确定局部MCP-1表达对肾脏的影响 病理学，并研究MCP-1是否恢复了 MCP-L缺乏MRL-FASLPR肾脏中的离散区域。我们将确定是否 NZM241O菌株中自身免疫性肾炎需要MCP-1。 3）建立 是否将MCP-1受体拮抗剂（MCP-1RA）传递到MRLFASLPR 肾脏可防止受伤。我们建议：将MCP-LRA交付到一个离散的部分 使用离体逆转录病毒基因转移以及整个肾脏的肾脏 在体内使用慢病毒载体。我们将建立关键时期 MCP-1 R通过四环素反式激活器系统进行切换交付 在肾炎进展过程中，McP-IRA“开关”的速度。 4） 建立趋化因子的作用，该趋化因子在MRL-FASLPR中与MCP-1共享CCR2 老鼠。我们建议比较缺乏MRL-FASLPRSTRAS的肾脏疾病 CCR2和MCP-L确定其他MCP是否为电势 肾脏疾病的靶标。