The role and regulation of pericytes in remodeling the periarterial niche during nephrogenesis

项目总结/摘要 慢性肾脏疾病是美国的主要死因，并给美国人民带来巨大负担。 医疗保健系统。许多慢性肾病病例最终导致肾纤维化， 其特征在于肌成纤维细胞沉积过量的细胞外基质（ECM），并有助于最终的 器官衰竭最近的研究已经确定了肾周细胞，一种血管周围细胞， 小血管如毛细血管的内皮细胞，作为纤维化中肌成纤维细胞的来源。尽管如此 在一个主要的疾病过程中的特征性作用，很少有人知道的发展起源或作用， 周细胞 我们发现了一种新的周细胞群，它们只在发育过程中围绕动脉， 我们称之为动脉周细胞我们用鼠遗传学方法鉴定了这些周细胞的起源， 记者说此外，我们已经确定了周细胞迁移的一个潜在调节因子，它存在于 肾脏发育过程中动脉周细胞的这种临时引导意味着在 动脉生成我们的初步数据表明，周细胞可能需要胶原蛋白的生产， 血管平滑肌分化在肾发生，反映其致病作用的纤维化。因此，在本发明中， 本项目的总体目标是确定动脉周细胞在肾发生过程中重塑的作用。 动脉周围小生境的ECM支持血管平滑肌成熟，以及阐明 在发育过程中，它们的定位机制受到调节。我们将利用小鼠遗传谱系追踪 除了免疫荧光染色和尖端原位杂交技术， 动脉周细胞在整个发育过程中的起源、命运和基因表达。我们会有选择地切除 周细胞，以评估它们在动脉生成和平滑肌覆盖中的需求。最后我们将 利用体外模型阐明ECM的周细胞分泌所需的细胞内相互作用， 平滑肌细胞成熟，以及阐明周细胞迁移的调节机制。 总的来说，这些研究将描述周细胞在发育过程中的新作用，并阐明 在疾病过程中可能失调的分子机制，如肾纤维化。这些信息 可能会为慢性肾脏疾病或再生医学的未来治疗提供信息， 随着肾脏疾病在美国和国外的流行率的增长，迫切需要这种药物。

PROJECT SUMMARY/ABSTRACT Chronic kidney disease is a leading cause of death in the United States and places an immense burden on the healthcare system. Many cases of chronic kidney disease eventually result in renal fibrosis, which is characterized by deposition of excess extracellular matrix (ECM) by myofibroblasts and contributes to eventual organ failure. Recent studies have identified renal pericytes, a type of perivascular cell that surrounds endothelial cells of small vessels such as capillaries, as the source of myofibroblasts in fibrosis. Despite this characterized role in a major disease process, little is known about the developmental origin or role of pericytes. We have characterized a novel population of pericytes that surrounds arteries only during development, which we call periarterial pericytes. We have characterized the origin of these pericytes using murine genetic reporters. Furthermore, we have identified a potential regulator of pericyte migration, which is present in the kidney during development. This temporary guidance of periarterial pericytes implies an important role in arteriogenesis. Our preliminary data suggest that pericytes may be required for collagen production and vascular smooth muscle differentiation during nephrogenesis, mirroring their pathogenic role in fibrosis. Thus, the overall goal of this project is to define the role of periarterial pericytes during nephrogenesis in remodeling the ECM of the periarterial niche to support vascular smooth muscle maturation, as well as to elucidate the mechanism by their localization is regulated during development. We will utilize murine genetic lineage tracing tools, in addition to immunofluorescence staining and cutting edge in situ hybridization techniques, to trace the origin, fate, and gene expression of periarterial pericytes throughout development. We will selectively ablate pericytes in vivo to assess their requirement in arteriogenesis and smooth muscle coverage. Finally, we will utilize in vitro models to clarify intracellular interactions that are required for pericyte secretion of ECM and smooth muscle cell maturation, as well as to elucidate the mechanism by which pericyte migration is regulated. Collectively, these studies will characterize a novel role of pericytes during development, as well as elucidate molecular mechanisms that may be dysregulated in disease processes such as renal fibrosis. This information may inform future therapies for chronic kidney disease or regenerative medicine efforts, both which will be badly needed as the prevalence of kidney disease grows in the United States and abroad.