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

项目摘要/摘要 慢性肾脏疾病是美国主要的死亡原因，给人们带来巨大的负担 医疗保健系统。许多慢性肾脏疾病最终会导致肾纤维化，这是 以肌成纤维细胞沉积过多的细胞外基质(ECM)为特征，并有助于最终 器官衰竭。最近的研究已经确定了肾周细胞，这是一种围绕在周围的血管周围细胞 毛细血管等小血管的内皮细胞，作为纤维化中肌成纤维细胞的来源。尽管如此 以在重大疾病过程中的作用为特征，对其发育起源或作用知之甚少 周细胞。 我们已经描述了一种新的周细胞群体，它只在发育过程中围绕动脉，这 我们称之为动脉周细胞。我们已经用小鼠基因来表征这些周细胞的起源。 记者。此外，我们已经确定了周细胞迁移的一个潜在的调节因子，它存在于 肾脏处于发育过程中。这种对动脉周围周细胞的暂时指导暗示着在 动脉形成。我们的初步数据表明，周细胞可能是胶原蛋白产生和 肾发生过程中的血管平滑肌分化，反映了它们在纤维化中的致病作用。因此， 这个项目的总体目标是确定动脉周细胞在肾脏形成过程中在重塑中的作用。 动脉周围龛的细胞外基质支持血管平滑肌成熟，并阐明 机制通过它们的局部化在发育过程中被调节。我们将利用小鼠的遗传谱系追踪 工具，除了免疫荧光染色和尖端的原位杂交技术，以追踪 动脉周细胞的起源、命运和发育过程中的基因表达。我们将选择性地消融 体内周细胞，以评估它们在动脉生成和平滑肌覆盖方面的需求。最后，我们会 利用体外模型阐明周细胞分泌ECM所需的细胞内相互作用 本研究的目的是为了更好地研究血管内皮细胞的成熟，以及阐明周细胞迁移的调控机制。 总而言之，这些研究将描述周细胞在发育过程中的新角色，并阐明 在肾脏纤维化等疾病过程中可能被失调的分子机制。此信息 可能会为未来的慢性肾脏疾病治疗或再生医学努力提供参考，这两者都将是 随着肾脏疾病在美国和国外的流行，人们迫切需要这种药物。

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.