Pathogenic reciprocal interplay between cyst epithelium and myofibroblasts in polycystic kidney disease

多囊肾病中囊肿上皮和肌成纤维细胞之间的致病相互作用

• 批准号: 10608350
• 负责人: Reena Rao
• 金额: $ 50.67万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608350
• 关键词: Actins; Autophagocytosis; Autosomal Dominant Polycystic Kidney; Catabolic Process; Cell Communication; Cell Nucleus; Cell secretion; Cells; Chronic Disease; Conditioned Culture Media; Cyst; Cystic kidney; Data; Development; Disease Progression; End stage renal failure; Environment; Epithelial Cell Proliferation; Epithelial Cells; Epithelial cyst; Epithelium; Extracellular Matrix; Fibroblasts; Fibrosis; Functional disorder; Ganciclovir; Gene Deletion; Genes; Glutamine; Goals; Growth; Growth Factor; HIF1A gene; Human; Hypoxia; Hypoxia Inducible Factor; Immune; Impairment; In Vitro; Inflammation; Inherited; Kidney; Kidney Diseases; Knockout Mice; Mediating; Metabolism; Modeling; Mus; Myofibroblast; Nutrient; Organ; Pathogenicity; Pathologic; Play; Polycystic Kidney Diseases; Population; Proliferating; Regulation; Reporting; Research; Research Personnel; Role; Smooth Muscle; System; Testing; Thymidine Kinase; Tissues; Transgenic Organisms; chemokine; cytokine; in vitro testing; inhibition of autophagy; innovation; interstitial; kidney fibrosis; knockout gene; metabolomics; mouse model; novel; paracrine; treatment strategy; tumor; uptake

PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is an inherited kidney disease. The goal of this study is to determine if renal interstitial myofibroblasts play an essential role in ADPKD progression by undergoing autophagy and supplying nutrients that support cyst growth. While myofibroblasts are known to be important for renal fibrosis, our novel preliminary data suggests that myofibroblasts could directly regulate cyst growth in ADPKD kidneys by paracrine mechanisms. We found that secreted factors from cyst epithelial cells such as lactate, stimulate autophagy in myofibroblasts by a hypoxia-inducible factor (HIF1α)- dependent mechanism. Moreover, factors such as glutamine, secreted by ADPKD renal myofibroblast- by a HIF1α and autophagy dependent mechanism increased proliferation and cyst growth of human ADPKD cyst epithelial cells. Hence, we hypothesize that, cyst epithelial cells use paracrine mechanisms to induce autophagy in myofibroblasts, leading to secretion of cyst-growth promoting factors. Aim 1 will test if reducing the renal myofibroblast population will reduce cyst growth in mouse ADPKD kidneys. Aim 2 will determine the role of myofibroblast-specific HIF1α in cyst growth. In Aim 3, the role of myofibroblast-specific autophagy and metabolites secreted by myofibroblasts in cyst-expansion will be examined. In addition to the innovative hypothesis, our studies will use state of the art transgenic and tissue specific gene knockout mice and identify myofibroblast -specific secreted factors, important for regulation of cyst growth in ADPKD kidneys. These studies are significant because we test a novel and fundamental mechanism by which cyst epithelial cells manipulate myofibroblasts in their microenvironment to produce nutrients to support cyst growth and disease progression in ADPKD. Although altered metabolism, hypoxia, autophagy, and the role of the cyst microenvironment in cyst growth are emerging fields in ADPKD pathophysiology, the importance of myofibroblast-mediated regulation of cyst growth is unclear. This study will build on our lab's strengths in studying ADPKD pathophysiology, with co-investigators and collaborators who are leaders in the fields of PKD, hypoxia, metabolism or autophagy. The results are expected to lead to development of better therapies for ADPKD.

项目摘要/摘要 常染色体显性多囊性肾脏疾病（ADPKD）是一种遗传性肾脏疾病。这项研究的目的是 确定肾脏间质肌纤维细胞是否通过进行ADPKD的进展中起着至关重要的作用 自噬并提供支持囊肿生长的营养。众所周知，肌纤维细胞很重要 肾纤维化，我们的新型初步数据表明，肌纤维细胞可以直接调节囊肿的生长 ADPKD KIDSNEYS通过旁分泌机制。我们发现来自囊肿上皮细胞的分泌因子，例如 裂缝，通过缺氧诱导因子（HIF1α） - 依赖机制刺激肌纤维细胞自噬。 此外，由ADPKD肾脏成肌纤维细胞分泌的因素，由HIF1α和自噬分泌 依赖机制增加了人ADPKD囊肿上皮细胞的增殖和囊肿生长。因此， 我们假设，囊肿上皮细胞使用旁分泌机制在肌纤维细胞中诱导自噬， 导致囊肿增长促进因素的分泌。 AIM 1将测试是否减少肾脏肌纤维细胞种群 将减少小鼠ADPKD肾脏中的囊肿生长。 AIM 2将确定肌纤维细胞特异性HIF1α的作用 在囊肿生长中。在AIM 3中，肌纤维细胞分泌的肌纤维细胞特异性自噬和代谢产物的作用 在囊肿中将进行检查。除了创新的假设外，我们的研究还将使用最先进的状态 转基因和组织特异性基因基因敲除小鼠并识别肌纤维细胞特异性分泌因素，重要 用于调节ADPKD肾脏中的囊肿生长。这些研究很重要，因为我们测试了一本小说， 囊肿上皮细胞在其微环境中操纵肌纤维细胞的基本机制 产生营养以支持ADPKD中的囊肿生长和疾病进展。尽管新陈代谢改变，但 缺氧，自噬和囊肿微环境在囊肿生长中的作用是ADPKD的新兴领域 病理生理学，肌纤维细胞介导的囊肿生长调节的重要性尚不清楚。这项研究会 基于我们实验室在研究ADPKD病理生理学方面的优势，与共同研究者和合作者 PKD，缺氧，代谢或自噬领域的领导者。预计结果将导致发展 ADPKD的更好疗法。