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 常染色体显性遗传性多囊肾病(ADPKD)是一种遗传性肾病。这项研究的目标是 肾间质肌成纤维细胞是否在ADPKD进展中起重要作用 自噬和提供支持包囊生长的营养物质。虽然已知肌成纤维细胞在 肾纤维化，我们新的初步数据表明，肌成纤维细胞可以直接调节肾脏囊性变的生长。 ADPKD肾脏通过旁分泌机制。我们发现囊上皮细胞分泌的因子，如 乳酸，通过缺氧诱导因子(HIF1α)依赖的机制刺激肌成纤维细胞的自噬。 此外，由ADPKD肾肌成纤维细胞分泌的谷氨酰胺等因子-由HIF1α和自噬 依赖机制促进人ADPKD囊上皮细胞的增殖和囊壁生长。因此， 我们假设，囊上皮细胞使用旁分泌机制诱导肌成纤维细胞的自噬， 导致分泌促囊生长因子。目标1将测试是否减少肾脏肌成纤维细胞的数量 会减少ADPKD小鼠肾脏的囊性生长。AIM 2将确定肌成纤维细胞特异性缺氧诱导因子1α的作用 在包囊生长过程中。在目标3中，肌成纤维细胞特异性自噬和肌成纤维细胞分泌的代谢物的作用 在囊性扩张方面将进行检查。除了创新假设外，我们的研究还将使用最先进的技术 转基因和组织特异性基因敲除小鼠并鉴定肌成纤维细胞特异性分泌因子，重要 用于调节ADPKD肾脏的囊性生长。这些研究意义重大，因为我们测试了一部小说和 囊上皮细胞在其微环境中操纵肌成纤维细胞的基本机制 生产营养物质以支持ADPKD的包囊生长和疾病进展。虽然改变了新陈代谢， 低氧、自噬和囊微环境在囊生长中的作用是ADPKD的新兴领域。 在病理生理学方面，肌成纤维细胞介导的囊壁生长调控的重要性尚不清楚。这项研究将 以我们实验室在研究ADPKD病理生理学方面的优势为基础，与下列人员合作研究 在PKD、缺氧、新陈代谢或自噬领域的领导者。预计结果将导致发展 更好的治疗ADPKD的方法。