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.

尿路上皮生物学的关键范式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，膀胱膨胀可以触发细胞质梭形囊泡与顶部表面融合，而 膀胱收缩可能导致一些顶部表面膜的检索以改革梭形囊泡。 该范式的核心是一组尿路上皮特异性蛋白，乌罗皮蓝蛋白，它们是主要的 尿路上皮分化产品。乌罗蓝蛋白形成16 nm颗粒，六边形，形成2D晶体 几乎构成整个尿路上皮表面以及梭形囊泡的尿路上皮斑块。我们 以前已经证明尿紫红素有助于膀胱屏障功能，乌洛普拉金的缺陷可能 导致严重的肾脏发育不良，乌洛普拉金表达的停止与不利的膀胱有关 癌症的结果，泌尿普拉氏蛋白IA是尿路病性大肠杆菌的尿路上皮受体。这些发现 不仅建立乌洛飞金人在膀胱屏障功能中的基本重要性，而且还建立 参与主要的泌尿科疾病。尽管尿素在尿路上皮生物学中可能具有重要意义 和疾病，对于这些蛋白质如何组装成尿皮斑块，如何交付的疾病，几乎不知道 有选择地到顶端细胞表面，以及如何从顶部表面进行内吞/检索。鉴于 最近的数据表明，与尿素发病蛋白的大肠杆菌结合在与尿素IA受体结合后，侵入 伞状细胞通过乌罗蓝蛋白内吞途径，至关重要的是，我们从根本上更好地理解这些途径是至关重要的 重要的尿路上皮细胞过程及其调节。我们在研究uroplakin的好处 贩运是因为我们最近确定了主要的尿路上皮斑块相关蛋白Mal，可能是 参与尿局的顶端递送。同样，我们发现了一种小说，尿路上皮特异性 分类Nexin，暂定命名为SNX32，可能参与了乌洛普拉金的检索。因此，我们的目标 在下一个资金期间的研究将更好地理解：（i）乌洛飞金斯如何聚集成2D 结晶斑； （ii）如何将尿素粉传递到顶部表面； （iii）如何检索乌洛飞金蛋白 降解和/或回收。我们的结果应产生对膀胱屏障机制的新见解 功能，可逆的尿路上皮表面积调整以及包括尿路在内的泌尿科疾病 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起关键作用。我们的 提出的关于静脉受体的尿路上皮斑块是如何的研究 组装，输送到尿路上皮表面并检索以降解。这些 研究可能对尿路感染，间质膀胱炎有重要影响 尿路阻塞和肾脏腺泡。