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：白细胞大量涌入是进行性肾脏疾病的常见现象。 靶向负责将白细胞募集到体内的特定分子 肾脏提供了一种阻止组织进行性损伤的治疗策略。 单核细胞趋化蛋白-1 (MCP-1) 属于“趋化因子”家族 它将白细胞吸引到炎症目标组织。 MCP-l是 在进展性肾病过程中肾实质细胞大量表达 受伤。 MCP-1 的阻断减少了活化巨噬细胞的流入，从而 使肾小管免受巨噬细胞介导的急性细胞凋亡破坏 肾毒性血清肾炎。 MRL-Faslpr 模型很容易识别 进行性肾病的治疗目标，因为肾脏破坏是 自发的、稳步进行的、可预测的、致命的，并且与 人类疾病。 MRL-Faslpr 模型中的肾脏疾病很复杂，包括 肾小球、肾小管和血管周围损伤，并伴有强烈的 巨噬细胞和淋巴细胞涌入。 MCP-1 在以下细胞中强烈表达： MRL-Faslpr 肾脏在受伤前，并随着疾病的进展而增加。我们 构建了 MCP-1 遗传缺陷的 MRL-Faslpr 菌株， 确定缺乏 MCP-1 的小鼠比野生型小鼠寿命长得多。 我们建议使用遗传方法来检验 MCP-1 是一种 进行性自身免疫性肾病的治疗靶点。我们建议：1) 确定自身免疫性肾病是否需要 MCP-1。我们将 确定 MCP-1(-/-) 缺陷 MRL-Faslpr 小鼠是否受到保护 肾脏疾病，并确定保护是否仅限于肾脏，或 是系统性的。 2) 确定MCP-1进入肾脏的递送是否放大 或引发进行性肾病。使用逆转录病毒基因转移方法 其提供MCP-1持续递送至肾脏的离散区域， 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 是否能在一定时间内恢复病理学 MCP-1 缺陷 MRL-Faslpr 肾脏中的离散区域。我们将确定是否 NZM241O 菌株的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) 递送至 MRLFaslpr 肾脏可以防止受伤。我们建议： 将 MCP-lra 交付给 使用离体逆转录病毒基因转移至肾脏并遍及整个肾脏 在体内使用慢病毒载体。我们将确定关键时期 通过四环素反式激活系统阻断 MCP-1 r 以切换递送 MCP-ira 在肾炎进展过程中的各个阶段“时断时续”。 4） 确定与 MCP-1 共享 CCR2 的趋化因子在 MRL-Faslpr 中的作用 老鼠。我们建议比较缺乏 MRL-Faslprs 菌株的肾脏疾病 CCR2 和 MCP-l 以确定其他 MCP 是否具有潜在治疗性 肾脏疾病的目标。