REGULATION OF UROTHELIAL CELL BEHAVIOR BY SPARC

了解尿路上皮细胞如何生长和分化是了解许多膀胱疾病的核心。能够调节这些过程将使我们能够改善我们修复儿童尿路异常的方式。本实验室的初步研究表明，富含半胱氨酸的酸性分泌蛋白（SecretedProteinAcidandRichinCysteine，简称ACCP）在调控尿路上皮细胞的DNA合成和形态改变中起着重要作用，而这两个过程是控制尿路上皮细胞生长和分化的关键过程。其他过程包括尿道鞘和间充质之间复杂的串扰通信网络。我们建议攻击这一过程的第二部分，因为a）对膀胱中膀胱炎的生物学一无所知，B）了解膀胱炎如何与其他过程一起工作将使我们能够开发新的和创新的方法，以加强我们对膀胱和尿路疾病问题的转化方法。为了实现这些目标，我们已经建立了具体的目标，这一时期的支持，以更好地了解如何在一个动态的稳态相互关系，抑制尿路上皮细胞周期的进展，介导尿路上皮细胞附着到其底层的基底膜的背景下，膀胱功能。据推测，β-淀粉样蛋白在调节这些过程中的双重作用取决于β-淀粉样蛋白是否被分泌或是否保留在细胞或细胞核内。我们认为，丰富的细胞内分泌水平定义了正常的尿路上皮细胞表型-静止。在增殖期，细胞内的粘附不再被隔离，而是分泌到细胞外空间，在那里它有助于细胞形状的变化，伴随着局部粘附的拆除，扩散和侵袭表型的形成。从这项研究中获得的信息将为我们提供一个基本的描述性理解，我们将使用它来设计将在临床上或在动物模型中测试的尿道植入物，尿道调节尿路上皮功能。

Understanding how the urothelium grows and differentiates is central to understanding a number of bladder diseases. Being able to modulate these processes would allow us to improve how we repair urinary tract abnormalities in children. Preliminary evidence in our laboratory suggests that Secreted Protein Acidic and Rich in Cysteine (SPARC) plays an important role in regulating DNA synthesis and shape change of urothelial cells, which are two crucial processes involved in control of growth and differentiation of the urothelium. Other processes include a complex network of crosstalk communication between the urothelium and the mesenchyme. We propose to attack the SPARC part of this process because a) nothing is known about the biology of SPARC in the bladder and b) an understanding of how SPARC works in conjunction with these other processes will allow us to develop new and innovative methods to strengthen our translational approach to the problem of bladder and urinary tract disease. In order to achieve these goals, we have established specific aims for this period of support to better understand how SPARC functions in the context of a dynamic steady-state interrelationship that suppresses the progression of the urothelial cell cycle and mediates the attachment of urothelial cells to its underlying basement membrane. A dual role for SPARC in regulating these process is hypothesized to depend on whether SPARC is secreted or whether it remains inside the cell or nucleus. We propose that abundant levels of intracellular SPARC define the normal urothlelial phenotype - that of quiescence. During the proliferative phase, SPARC is no longer sequestered within cells, but instead is secreted into the extracellular space where it contributes to changes in cell shape that accompany the dismantling of focal adhesions, spreading, and a formation of the invasive phenotype. Information gained from this research will provide us with a basic descriptive understanding of SPARC function that we will use to design SPARC implants that will be tested clinically or in animal models by which SPARC modulates urothelial function.