Development of an in vitro model of the glomerular filtration barrier using cell sheet engineering

复杂的体外模型开始为研究复杂器官的特定亚结构表型提供更明确的工具。目前，还没有体外的肾小球模型来展示这种复杂结构中特定细胞类型的一系列特征，或者使其能够作为一个过滤单位。虽然细胞系作为单细胞或共培养系统存在，但它们不能提供肾小球滤过单位的全部基因/表型，也不存在于三维结构中。这种模型的发展将使研究体外环境中肾小球的基本生物学，以及不同类型的细胞如何在该结构内相互作用形成功能性滤过屏障。这也将减少动物实验模型研究足细胞/肾小球生物学的需要。此外，尽管这种模型被认为是一个巨大的挑战，但它可以与肾单位肾小管培养相结合，从而形成一个完整的肾脏体外模型。该项目的范围将是利用3D培养技术、流体/微流体和共培养技术，对肾小球内皮细胞(足细胞)的器官类型结构和功能进行建模。曼彻斯特大学已经在该小组内部建立了一项技术--细胞板工程，这将有助于模型的组装。成功的候选人将在建立复杂的体外模型方面获得宝贵的第一手经验，使用各种显微技术，并对肾脏生物学/生理学和病理生理学有深入的背景知识。

Complex in vitro models are starting to provide more defined tools for the study of specific substructural phenotypes for complex organs. At present there are no in vitro models of the glomerulus that demonstrate the range of characteristics indicative of the specific cell types within this complex structure, or enable its functionality as a filtration unit. Although cell lines exist, as single cell or co-culture systems, they do not offer the full genotype/phenotype of the glomerular filtration unit, nor do not they exist within a 3-dimensional architecture.The development of such a model would enable the study of the basic biology of the glomerulus in an in vitro setting and how the various cell types interact within this structure to form a functional filtration barrier. This would also reduce the need for animal experimental models to study podocyte/glomerular biology. Furthermore, although recognised as a significant challenge, such a model could lend itself for association with nephron tubular cultures enabling the formation of an integrated in vitro model of the kidney. The remit of the project would be to model the organotypic structure and function of epithelial cells (podocytes) within the glomerulus in association with the glomerular endothelium, using 3D culture technologies, fluidics/microfluidics and co-culture. Cell sheet engineering, a technique already established within the group at the University of Manchester, will be available to aid the assembly of the model. The successful candidate would gain valuable first-hand experience in building complex in vitro models, the use of various microscopy techniques, and a deep background knowledge of kidney biology/physiology and pathophysiology