Biochemistry of Urothelial Differentiation

尿路上皮生物学中的一个关键范例是尿路上皮伞细胞可以可逆地调整其顶端细胞表面。 区域。因此，膀胱扩张可以触发细胞质梭形小泡与根尖表面融合，而 膀胱收缩可导致一些根尖表面膜恢复，以改造梭形小泡。 这一模式的核心是一组尿路上皮特异的蛋白质，即尿路上皮细胞因子，它们被作为主要的 尿路上皮分化产物。尿路蛋白形成16纳米颗粒，六角形堆积，形成2D晶体 几乎构成整个尿路上皮尖表面的尿路上皮斑以及梭形小泡。我们 此前已证明尿路蛋白有助于膀胱屏障功能，尿路蛋白缺陷可能 导致严重肾发育不良，尿路蛋白表达停止与膀胱不适有关 Uroplakin Ia是致尿路病原性大肠杆菌的尿路上皮受体。这些发现 不仅确定尿路蛋白在膀胱屏障功能中的基本重要性，而且确定其可能的作用。 涉及重大泌尿系统疾病。尽管尿板蛋白在尿路上皮生物学中具有潜在的重要性 和疾病，这些蛋白如何组装成尿路上皮斑块，它们是如何传递的，人们知之甚少 选择性地到根尖细胞表面，以及它们是如何内吞/从根尖表面取回的。给定 最近的数据表明，致尿性大肠杆菌在与尿路蛋白Ia受体结合后，入侵到 伞状细胞通过Uroplakin内吞途径，我们从根本上更好地理解这些是至关重要的 重要的尿路上皮细胞过程及其调控。我们处于研究尿路拉伤的绝佳位置 因为我们最近发现了一种主要的尿路上皮斑块相关蛋白MAL，它很可能是 参与输尿管的顶端输液。类似地，我们发现了一种新颖的，尿路上皮细胞特异的 分类Nexin，暂命名为SNX32，可能参与尿路蛋白检索。因此，我们的目标是 下一个资助期的研究是为了更好地了解：(I)尿路蛋白是如何组装成2D的 结晶斑块；(Ii)尿板如何被输送到根尖表面；以及(Iii)如何回收尿板 降解和/或回收。我们的结果应该对膀胱屏障的机制有新的见解。 功能、可逆性尿路上皮面积调节以及包括尿路在内的泌尿系统疾病 感染。叙述性 尿路上皮斑是覆盖在膀胱尖表面的独特结构。 尿路上皮细胞，在膀胱屏障功能和细菌感染中起关键作用。我们的 关于含有细菌受体的尿路上皮斑块是如何 组装，输送到尿路上皮顶端表面，并回收用于降解。这些 研究对尿路感染、间质性膀胱炎、 尿路梗阻和肾发育不全。

A key paradigm in urothelial biology is that urothelial umbrella cells can reversibly adjust its apical cell surface area. Thus bladder expansion can trigger the cytoplasmic fusiform vesicles to fuse with the apical surface, while bladder contraction can lead to the retrieval of some apical surface membranes to reform fusiform vesicles. Central to this paradigm is a group of urothelium-specific proteins, the uroplakins, that are made as major urothelial differentiation products. Uroplakins form 16-nm particles packed hexagonally to form 2D crystals of urothelial plaques that constitute almost the entire urothelial apical surface as well as the fusiform vesicles. We have previously demonstrated that uroplakins contribute to bladder barrier function, that uroplakin defects may lead to severe renal dysplasia, that cessation of uroplakin expression is associated with unfavorable bladder cancer outcome, and that uroplakin Ia is the urothelial receptor for uropathogenic E. coli. These findings establish not only the fundamental importance of uroplakins in bladder barrier function, but also their possible involvements in major urological diseases. Despite the potential importance of uroplakins in urothelial biology and diseases, little is known about how these proteins assemble into urothelial plaques, how they are delivered selectively to the apical cell surface, and how they are endocytosed/retrieved from the apical surface. Given the recent data suggesting that uropathogenic E. coli, after binding to uroplakin Ia receptor, invade into the umbrella cells via the uroplakin endocytic pathway, it is crucial that we better understand these fundamentally important urothelial cellular processes and their regulation. We are in an excellent position to study uroplakin trafficking because we have recently identified a major urothelial plaque-associated protein, MAL, that is likely to be involved in the apical delivery of uroplakins. Similarly, we have discovered a novel, urothelium-specific sorting nexin, tentatively named SNX32, that may be involved in uroplakin retrieval. Thus, the goals of our studies during the next funding period are to better understand: (i) how uroplakins assemble into a 2D crystalline plaque; (ii) how uroplakins are delivered to apical surface; and (iii) how uroplakins are retrieved for degradation and/or recycle. Our results should yield new insights into the mechanisms of bladder barrier function, reversible urothelial surface area adjustment, as well as urological diseases including urinary tract infection. Narrative Urothelial plaques are unique structures covering the apical surface of urinary bladder urothelium, and play key roles in bladder barrier function and bacterial infection. Our proposed studies on how the urothelial plaques, that harbor the bacterial receptor, are assembled, delivered to the urothelial apical surface, and retrieved for degradation. These studies can have important implications for urinary tract infection, interstitial cystitis, urinary tract obstruction and renal adysplasia.