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Novel regulatory mechanisms of the glomerular endothelium

肾小球内皮的新调节机制

基本信息

批准号：
10006881
负责人：
JANOS PETI-PETERDI
金额：
$ 46.3万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006881
关键词：
Adult Affect Albumins Albuminuria Angiogenic Factor Angiogenic Proteins Animal Model Biological Assay Blood Blood Vessels Brain Cardiovascular Diseases Cell Culture Techniques Cell Line Cell Lineage Cells Chief Cell Chronic Kidney Failure Code Development Disease Disease Progression Disease model Endothelial Cells Endothelium Enzyme-Linked Immunosorbent Assay Equilibrium Extravasation Fibrosis Fibrous capsule of kidney Foundations Functional disorder Genes Genetic Glomerular Capillary Health Heart Histology Hormones Implant In Vitro Injury Juxtaglomerular Apparatus Juxtaglomerular Cell Kidney Kidney Diseases Knock-out Knockout Mice Knowledge Laboratories Macula densa Maintenance Measurement Mediating Methods Mus Natural regeneration Nephrectomy PTGS2 gene Paracrine Communication Pathogenicity Pathology Pharmacology Phenotype Physiological Plasma Play Population Production Regulation Research Role Signal Transduction Sodium Chloride Structure Technology Testing Tissues Transgenic Mice Visual WNT Signaling Pathway angiogenesis base cardiovascular health cell injury cell type comorbidity diabetic dietary salt gain of function glomerular endothelium imaging approach implantation improved in vivo intravital imaging loss of function mortality mouse model multiphoton microscopy novel novel diagnostics novel therapeutics paracrine precursor cell programs regenerative therapy repaired response salt intake stem cells uptake

项目摘要

Glomerular endothelial cells play pivotal roles in the maintenance of the normal structure and function of the healthy glomerulus, and also in the development of glomerular injury in kidney diseases. However, our knowledge of the mechanisms that constantly maintain and regenerate the glomerular endothelium after injury have been limited, due to the inaccessibility of this cell type and lack of in vivo research technologies. Our laboratory has recently developed novel transgenic mouse models and an intravital imaging approach using serial multiphoton microscopy (MPM) of the same glomerulus over several days-weeks to quantitatively visualize and track the fate and function of the same single glomerular endothelial cells in the intact living kidney. This technical advance provided visual clues on the development of clonal endothelial cell clusters at the glomerular vascular pole in response to dietary salt restriction and various types on glomerular injury, and suggested its control by the juxtaglomerular apparatus (JGA). In addition, the foundation of this proposal is our recent preliminary findings which suggested that macula densa (MD) cells of the JGA are novel chief organizers and master regulators of glomerular remodeling in the adult kidney. Gene profiling showed that MD cells produce novel secreted tissue remodeling factors that act in a paracrine fashion on resident progenitor cells. One of the top new MD genes responsible for this new glomerular remodeling program was identified as CCN1 (also known as Cyr61), coding for a secreted angiogenic protein that is known to target endothelial cells as well as other cell types. Our main hypothesis is that MD cells, via Wnt signaling-mediated synthesis and secretion of angiogenic proteins including CCN1, are major paracrine regulators of the glomerular endothelium. This project will use comprehensive experimental approaches including in vitro cell culture, new transgenic mouse models, fluorescently tagged cell lineages, cell fate tracking, in vivo disease models and serial MPM to investigate the angiogenic role, mechanisms, and importance of MD cells and CCN1 in glomerular endothelial maintenance and repair. The specific aims are to (i) Examine the role and mechanism of MD cells in the maintenance of normal glomerular capillary structure and function, (ii) Study the regulation of the MD cell angiogenesis promoting program, and (iii) Test for renal and cardiovascular disease modifying roles and mechanisms of MD cells.

肾小球内皮细胞在维持正常的结构和功能中起着关键作用在健康肾小球中，以及在肾脏疾病中肾小球损伤的发展中。然而，我们对不断维持和再生肾小球的机制的认识，由于这种细胞类型的不可接近性和缺乏体内免疫调节，我们的实验室最近开发了新的转基因小鼠模型，使用连续多光子显微镜（MPM）对同一肾小球进行活体成像，几天到几周的时间来定量地可视化和跟踪同一个单一的细胞的命运和功能。这一技术进步为研究肾小球内皮细胞的功能提供了直观的线索。肾小球血管极克隆性内皮细胞簇的发育对饮食的反应盐限制和各种类型对肾小球损伤的影响，并提出了肾小球损伤的控制此外，这项建议的基础是我们最近的初步研究结果，提出JGA的致密斑（MD）细胞是新的主要组织者和主要调节者基因分析显示MD细胞产生新的分泌的组织重塑因子以旁分泌方式作用于常驻祖细胞。负责这一新的肾小球重塑计划的顶级新MD基因被确定为CCN 1 (also称为Cyr61），编码已知靶向内皮细胞的分泌的血管生成蛋白我们的主要假设是MD细胞通过Wnt信号通路介导的合成和分泌血管生成蛋白，包括CCN 1，是肾小球的主要旁分泌调节因子。本项目将采用全面的实验方法，包括体外细胞培养，培养，新型转基因小鼠模型，荧光标记细胞谱系，细胞命运追踪，体内疾病模型和系列MPM，以研究MD的血管生成作用、机制和重要性细胞和CCN 1在肾小球内皮维护和修复中的作用。具体目的是（i）检查 MD细胞在维持正常肾小球毛细血管结构中的作用和机制，功能，（ii）研究MD细胞血管生成促进程序的调节，和（iii）测试肾功能。以及MD细胞对心血管疾病的调节作用和机制。