REGULATION OF UROTHELIAL CELL BEHAVIOR BY SPARC

了解尿路上皮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进我们修复儿童尿路异常的方式。我们实验室的初步证据表明，富含半胱氨酸的酸性分泌蛋白(SPARC)在调节尿路上皮细胞DNA合成和形态变化方面发挥着重要作用，这两个过程是控制尿路上皮细胞生长和分化的两个关键过程。其他过程包括尿路上皮和间充质之间的串扰通信的复杂网络。我们建议攻击这一过程的SPARC部分，因为a)对SPARC在膀胱中的生物学一无所知，以及b)了解SPARC如何与这些其他过程一起工作将使我们能够开发新的创新方法，以加强我们对膀胱和尿路疾病问题的翻译方法。为了实现这些目标，我们为这一时期的支持制定了具体的目标，以更好地了解SPARC如何在动态的稳态相互关系中发挥作用，这种相互关系抑制了尿路上皮细胞周期的进展，并介导了尿路上皮细胞与其底层基底膜的附着。SPARC在调节这些过程中的双重作用被假设取决于SPARC是分泌的还是留在细胞或细胞核内。我们认为，细胞内SPARC的丰富水平定义了正常的尿路上皮表型--静止型。在增殖期，SPARC不再被隔离在细胞内，而是分泌到细胞外空间，在那里它有助于改变细胞形状，伴随着局部粘连的拆除、扩散和侵袭性表型的形成。从这项研究中获得的信息将为我们提供对SPARC功能的基本描述性理解，我们将使用这些信息来设计SPARC植入物，这些植入物将在临床上或在SPARC调节尿路上皮功能的动物模型中进行测试。

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.