Targeting kidney resident macrophage niche filling to slow cystic kidney disease

项目摘要 我们的数据表明，肾脏常驻巨噬细胞(KRM)促进了多只小鼠的囊性肾脏疾病 而且在人类中也存在类似的KRM群体，这表明将这些细胞作为靶点 囊性肾病患者可能会有显著的治疗益处。然而，给出不可行的 患者KRM靶向抑制剂长期存在，因为这些抑制剂耗尽多个 组织，在那里它们的存在是基本的生物学功能所必需的，包括循环红细胞和 与感染作斗争。这一问题在囊性肾病患者中尤其相关。 经历了几十年的间歇性囊性生长时期。这些数据突显了这样一个事实，即一种组织 迫切需要具体的方法来耗尽KRM。在本应用程序中，我们建议研究利基 作为一种手段来开发一种组织特异性的方法，用于长期滞留的巨噬细胞的耗竭。 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 暂时性耗竭，这一过程所需的基因，以及暂时性耗竭对长期存活的影响。 足月囊肿生长。根据我们的初步数据，我们假设单核细胞需要CX3CR1- 依存性小窝充盈和囊性进展。这一假设将通过单核细胞特有的命运来检验。 作图小鼠追踪两种野生动物耗尽后单核细胞募集和植入KRM生态位的情况 型小鼠和囊性小鼠。在随后的目标中，我们将识别这一过程所需的基因，并测试 我们可以针对候选基因CX3CR1来延缓KRM的缝隙填充和减缓囊性疾病的想法。基于 我们令人兴奋的初步数据表明，靶向CX3CR1可能导致长期的肾脏特异性治疗。 长期滞留巨噬细胞衰竭。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，这两种疾病都是主要的医疗负担。 1

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