Biochemistry of Urothelial Differentiation

尿路上皮分化的生物化学

• 批准号: 8011809
• 负责人: Tung-Tien Sun
• 金额: $ 6.88万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-20 至 2011-01-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011809
• 关键词: Acute; Antibiotic Resistance; Antibodies; Apical; Apoptosis; Applications Grants; Area; Bacteria; Bacterial Infections; Binding; Biochemistry; Biological Process; Biology; Bladder; Bladder Urothelium; Blood; CDK6-associated protein p18; Cell Surface Proteins; Cell physiology; Cell surface; Cells; Clinical; Complex; Data; Defect; Dysplasia; Employee Strikes; Endocytosis; Epitopes; Escherichia coli; Exocytosis; Funding; Goals; Interstitial Cystitis; Invaded; Kidney; Lead; Little' s Disease; Location; MDCK cell; Malignant neoplasm of urinary bladder; Mediating; Membrane; Membrane Protein Traffic; Membrane Proteins; Microbe; Molecular Conformation; Names; Nature; New Territories; Outcome; Pathway interactions; Permeability; Physiological; Play; Positioning Attribute; Process; Protein Isoforms; Proteins; Recurrence; Recycling; Regulation; Retrieval; Role; Sorting - Cell Movement; Structure; Surface; System; Testing; Tight Junctions; Time; UPK2 gene; UPK3 gene; Urinary tract infection; Urination; Urine; Urologic Diseases; Uropathogenic E. coli; Urothelial Cell; Urothelium; Vesicle; Work; cDNA Library; in vivo; insight; nexin; novel; particle; receptor; sorting nexins; trafficking; urinary tract obstruction

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.

尿路上皮生物学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囊泡与顶端表面融合，而 膀胱收缩可导致一些顶端表面膜的恢复以重新形成梭状囊泡。 这个范式的核心是一组尿路上皮特异性蛋白质，即尿斑蛋白，它们是作为主要的 尿路上皮分化产品。尿斑蛋白形成六边形堆积的 16 nm 颗粒，形成 2D 晶体 尿路上皮斑块几乎构成整个尿路上皮顶端表面以及梭形囊泡。我们 之前已经证明尿斑蛋白有助于膀胱屏障功能，尿斑蛋白缺陷可能 导致严重的肾发育不良，尿斑蛋白表达的停止与不利的膀胱有关 癌症结果，并且尿斑蛋白 Ia 是尿路致病性大肠杆菌的尿路上皮受体。这些发现 不仅确定了尿斑蛋白在膀胱屏障功能中的根本重要性，而且还确定了它们的可能 涉及重大泌尿外科疾病。尽管尿斑蛋白在尿路上皮生物学中具有潜在的重要性 和疾病，人们对这些蛋白质如何组装成尿路上皮斑块以及如何传递知之甚少 选择性地到达顶端细胞表面，以及它们如何从顶端表面被内吞/回收。鉴于 最近的数据表明，尿路致病性大肠杆菌在与尿斑蛋白 Ia 受体结合后，侵入尿路 伞细胞通过尿斑蛋白内吞途径，我们从根本上更好地理解这些至关重要 重要的尿路上皮细胞过程及其调节。我们处于研究 uroplakin 的绝佳位置 贩运，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 参与尿斑蛋白的顶端递送。同样，我们发现了一种新颖的尿路上皮特异性 分选连接蛋白，暂定名为SNX32，可能参与尿斑蛋白修复。因此，我们的目标 下一个资助期间的研究旨在更好地了解：(i) uroplakins 如何组装成 2D 结晶斑块； (ii) 尿斑蛋白如何被递送至根尖表面； (iii) 如何回收尿斑蛋白 降解和/或回收。我们的结果应该会对膀胱屏障的机制产生新的见解 功能，可逆性尿路上皮表面积调整，以及泌尿系统疾病，包括尿路 感染。叙述 尿路上皮斑块是覆盖膀胱顶端表面的独特结构 尿路上皮，并在膀胱屏障功能和细菌感染中发挥关键作用。我们的 拟议的研究是关于含有细菌受体的尿路上皮斑块如何被 组装，输送到尿路上皮顶端表面，并回收进行降解。这些 研究对尿路感染、间质性膀胱炎、 尿路梗阻和肾发育不良。