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: 10518723
• 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/10518723
• 关键词: 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; Lead; Liver; Mus; Patients; Persons; Pharmacologic Substance; Pharmacology; Population; Process; Recycling; Renal function; Severities; Source; Synapses; Testing; Therapeutic; Tissues; Wild Type Mouse; base; experience; fighting; inhibitor; interest; macrophage; monocyte; mouse model; novel strategies; 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，肾驻留巨噬细胞（KRM）促进多个小鼠的囊性肾病 模型，并且在人类中存在类似的KRM群体，这表明靶向这些细胞， 患有囊性肾病的患者可能具有显著的治疗益处。但是，给 患者KRM靶向抑制剂很长一段时间，因为这些抑制剂消耗多个细胞中的驻留巨噬细胞， 组织，其中它们的存在是基本生物功能所必需的，包括回收红细胞， 抵抗感染这个问题在囊性肾病的情况下特别相关，因为患者 经历了几十年的间歇性囊肿生长期。这些数据强调了一个事实， 迫切需要具体办法来消除知识产权管理。在这个应用程序中，我们建议研究生态位 填充作为开发用于长期驻留巨噬细胞耗竭的组织特异性方法的手段。 然而，在我们实现这一目标之前，我们必须首先了解生态位填充的机制， 暂时性耗竭，这一过程所需的基因，以及暂时性耗竭对长期- 术语囊肿生长。基于我们的初步数据，我们假设Cx 3cr 1是单核细胞- 依赖性龛填充和囊肿进展。这一假设将使用单核细胞特异性命运进行检验。 在两种野生型中，在耗尽后，对小鼠进行定位以追踪单核细胞募集和移植到KRM小生境中。 型和囊性小鼠。在随后的目标中，我们将确定这一过程所需的基因，并测试这些基因的表达。 我们可以靶向候选基因Cx 3cr 1，以延迟KRM龛填充和减缓囊性疾病。基于 根据我们令人兴奋的初步数据，我们提出，靶向Cx 3cr 1可能会导致长期的肾脏特异性方法， 长期驻留巨噬细胞耗竭。这将对囊性肾病领域产生重大影响， 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。 这两种疾病都是主要的医疗负担。 1