Immune Cell and Epithelial Cell Interactions in Autosomal Dominant Polycystic Kidney Disease

项目总结 常染色体显性遗传性多囊肾病(ADPKD)是最常见的、具有潜在致死性的单基因肾病 疾病。影响1：400到1：1000的人，编码多囊蛋白-1(PC1)的PKD1和PKD2基因突变 和多囊蛋白-2分别导致从肾脏逐渐扩大的充满液体的囊泡的发展。 上皮细胞。这种扩张破坏了周围的肾组织，导致纤维化，并导致病情恶化。 最终需要透析或移植的肾功能。半数ADPKD患者将经历肾功能衰竭 在50岁之前失败，而且几乎没有什么治疗选择来防止这种发病机制。这些都是预防性的 由于对囊变过程的了解有限，缺乏解决方案，这意味着为什么囊肿形成和 是什么让它们随着时间的推移而恶化。免疫细胞可能参与了这一过程。先前的文献表明 巨噬细胞在囊腔起始和扩张中的作用，CD8+T细胞最近在发挥作用时出现 潜在的抗囊性作用。使用一种新的ADPKD转基因抑制模型，在该模型中 PC1的C末端尾巴是表达的，我会比较免疫细胞群中目前存在的非抑制 疾病模型和非囊性对照的抑制模型。我假设差异免疫 疾病模型之间的细胞图谱将揭示调节促囊变和抗囊变的因子 肾上皮细胞在ADPKD发病机制中的作用凭借卡普兰实验室和 来自工艺实验室的免疫学调查，我将研究免疫细胞在ADPKD发病机制中的作用 在使用体内干预策略的小鼠模型中，并通过流式细胞仪分析这些模型， 免疫荧光和单细胞测序方法。我试图在ADPKD中定义免疫细胞信号 并阐明该信号在ADPKD发病机制中的意义，以期确定免疫- 参与囊变的介导性因素。除了阐明细胞信号改变囊状细胞外 和ADPKD的纤维化表现，这项建议同时旨在识别免疫细胞特性 可以作为疾病的生物标志物，并为治疗和监测战略提供洞察。

PROJECT SUMMARY Autosomal dominant polycystic kidney disease (ADPKD) is the most common, potentially lethal, monogenic disease. Affecting 1:400 to 1:1000 people, mutations in PKD1 and PKD2 genes encoding polycystin-1 (PC1) and polycystin-2, respectively, lead to development of fluid-filled cysts that progressively expand from renal epithelial cells. This expansion damages surrounding kidney tissue, causing fibrosis, and leads to worsening kidney function that ultimately requires dialysis or transplant. Half of the ADPKD population will experience renal failure by the age of 50, and there are few treatment options to prevent such pathogenesis. These preventative solutions are lacking due to limited understanding into the process of cystogenesis, meaning why cysts form and what makes them worsen over time. Immune cells may contribute to this process. Prior literature has suggested a role for macrophages in cyst initiation and expansion, and CD8+ T cells have recently emerged as exerting a potential anti-cystogenic role. Using a novel transgenic suppression model of ADPKD in which a portion of the C-terminal tail of PC1 is expressed, I will compare the immune cell populations present in a non-suppressed disease model and the suppression model with non-cystic controls. I hypothesize that the differential immune cell landscapes between disease models will reveal pro-cystogenic and anti-cystogenic factors that regulate renal epithelial cells in ADPKD pathogenesis. With the expertise in ADPKD from the Caplan Lab and in immunological investigation from the Craft Lab, I will investigate the role of immune cells in ADPKD pathogenesis in murine models using in vivo interventional strategies, and analyze these models by flow cytometry, immunofluorescence, and single-cell sequencing approaches. I seek to define immune cell signaling in ADPKD and to elucidate the implications of this signaling for ADPKD pathogenesis, expecting to identify immune- mediated factors implicated in cystogenesis. In addition to elucidating cellular signaling that modifies the cystic and fibrotic manifestations of ADPKD, this proposal simultaneously aims to identify immune cell properties that could serve as disease biomarkers and provide insight into treatment and monitoring strategies.