Targeting kidney resident macrophage niche filling to slow cystic kidney disease

靶向肾脏常驻巨噬细胞生态位填充以减缓囊性肾病

• 批准号: 10705287
• 负责人: Kurt A Zimmerman
• 金额: $ 31.72万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705287
• 关键词: Acceleration; Acute Renal Failure with Renal Papillary Necrosis; Affect; Animal Model; Biological Process; Bone Marrow; Brain; Candidate Disease Gene; Cardiac; Cells; Chronic; Chronic Kidney Failure; Clinical; Communities; Cyst; Cystic Kidney Diseases; Data; Development; Disease; Disease Progression; Engraftment; Erythrocytes; Genes; Genetic Transcription; Goals; Growth; Healthcare; Human; Immunology; Infection; Infection prevention; Intervention; Kidney; Knockout Mice; Knowledge; Liver; Macrophage; Maps; Mus; Patients; Persons; Pharmacologic Substance; Population; Process; Proliferating; Recycling; Renal function; Severities; Source; Synapses; Testing; Therapeutic; Tissues; Wild Type Mouse; care burden; experience; fighting; inhibitor; interest; monocyte; mouse model; novel strategies; pharmacologic; recruit; targeted treatment

Project abstract Our data indicate that kidney resident macrophages (KRM) promote cystic kidney disease in multiple mouse models and that a similar population of KRM are present in humans suggesting that targeting these cells in patients with cystic kidney disease may have significant therapeutic benefits. However, it is not feasible to give patients KRM targeted inhibitors for long periods as these inhibitors deplete resident macrophages in multiple tissues, where their presence is required for basic biological functions including recycling red blood cells and fighting off infections. This problem is particularly relevant in the case of cystic kidney disease as patients experience periods of intermittent cyst growth over several decades. These data highlight the fact that a tissue specific approach to deplete KRM is desperately needed. In this application, we are proposing to study niche filling as a means to developing a tissue specific approach for long-term resident macrophage depletion. However, before we can accomplish this goal, we must first understand the mechanism of niche filling after temporary depletion, genes that are required for this process, and the influence of temporary depletion on long- term cyst growth. Based on our preliminary data, we hypothesize that Cx3cr1 is required for monocyte- dependent niche filling and cyst progression. This hypothesis will be tested using a monocyte-specific fate mapping mouse to track monocyte recruitment and engraftment into the KRM niche after depletion in both wild type and cystic mice. In subsequent aims, we will identify genes that are required for this process and test the idea that we can target a candidate gene, Cx3cr1, to delay KRM niche filling and slow cystic disease. Based on our exciting preliminary data, we propose that targeting Cx3cr1 may lead to a kidney specific approach for long- term resident macrophage depletion. This would have major impact on the cystic kidney disease field as well as any field in which KRM are involved in disease progression. This includes acute kidney injury and chronic kidney diseases, both of which are a major healthcare burden. 1

项目摘要 我们的数据表明，肾脏常驻巨噬细胞（KRM）促进多只小鼠的囊性肾病 模型中存在类似的 KRM 群体，这表明针对这些细胞 囊性肾病患者可能具有显着的治疗益处。然而，给予 患者 KRM 长期靶向抑制剂，因为这些抑制剂会消耗多个体内的常驻巨噬细胞 组织，它们的存在是基本生物功能所必需的，包括回收红细胞和 对抗感染。这个问题在囊性肾病的情况下尤其重要，因为患者 经历数十年间歇性囊肿生长的时期。这些数据强调了这样一个事实：组织 迫切需要采取具体方法来消耗 KRM。在此应用程序中，我们建议研究利基 填充作为开发长期驻留巨噬细胞耗竭的组织特异性方法的一种手段。 然而，在实现这一目标之前，我们必须首先了解生态位填充的机制。 暂时耗尽、该过程所需的基因以及暂时耗尽对长期的影响 足月囊肿生长。根据我们的初步数据，我们假设 Cx3cr1 是单核细胞所必需的 依赖的生态位填充和囊肿进展。该假设将使用单核细胞特异性命运进行检验 绘制小鼠图谱以跟踪野生环境中单核细胞的募集和植入到 KRM 生态位中的情况 型和囊性小鼠。在后续目标中，我们将识别该过程所需的基因并测试 我们认为我们可以针对候选基因 Cx3cr1 来延迟 KRM 生态位填充并减缓囊性疾病。基于 我们令人兴奋的初步数据表明，针对 Cx3cr1 可能会导致针对长期肾脏的特定方法 长期驻留巨噬细胞耗竭。这将对囊性肾病领域以及 KRM 参与疾病进展的任何领域。这包括急性肾损伤和慢性肾损伤 疾病，这两者都是主要的医疗负担。 1