Regulation and Function of Uroplankin Genes
尿板蛋白基因的调控和功能
基本信息
- 批准号:7468458
- 负责人:
- 金额:$ 28.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-01 至 2009-06-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAffectApicalAreaBacteriaBinding ProteinsBladderBladder DiseasesCaliberCell Surface ProteinsCellsCessation of lifeCytoplasmic ProteinDefectDiseaseEmployee StrikesEtiologyGenesGlycocalyxGlycoproteinsGrantHydronephrosisHyperactive behaviorInterstitial CystitisKnock-outLeadLightLip structureMalignant neoplasm of urinary bladderMediatingMembraneMembrane ProteinsMolecularMusNeonatalPathogenesisPermeabilityPlayProteinsRegulationRoleSignal TransductionStructureSurfaceTestingUPK2 geneUrinary tract infectionUrinationUrologic DiseasesUrotheliumVesico-Ureteral Refluxdesignhuman PHEMX proteinmemberparticlereceptortwo-dimensional
项目摘要
The apical surface of mammalian urothelium is almost completely covered by rigid-looking urothelial plaques consisting of 16 nm uroplakin particles that are hexagonally packed into two-dimensional crystals. Highly purified urothelial plaques are comprised of four major uroplakins (UP), i.e., uroplakin Ia (27 kDa), Ib (28 kDa), II (15 kDa) and III (47 kDa). The two tetraspanin members UPIa and UPIb interact preferentially with the two single transmembrane-domained uroplakins II and III, respectively, forming two uroplakin pairs
consisting of UPIa/II and UPIb/III. During the last grant period, we genetically ablated mouse genes encoding for uroplakins II and III. Mice deficient in these two major urothelial differentiation products have a grossly abnormal urothelium lacking typical umbrella cells; have abnormally small urothelial plaques; and suffer from vesicoureteral reflux, hydronephrosis and, in some cases, neonatal death. These results indicate that uroplakins are integral subunits of the urothelial plaques which contribute to the permeability barrier function, and that urothelial defects may play a role in certain urinary tract diseases. Little is known, however, about how uroplakin defects may affect urothelial and bladder function as a whole, how uroplakins interact with
cytoplasmic and other membrane-associated proteins, and how surface-accessible are the uroplakin receptors to the uropathogenic bacteria. The proposed studies in this Project will attempt to answer some of these questions, by studying how the ablation of uroptakin genes affects the permeability barrier and micturition functions of the bladder (Aim 1); how uroplakins interact with some cytoplasmic proteins that may play a role in mediating uroplaldn:cytosketetal interaction and signal transduction (Aim 2); and how accessible uroplakin molecules are on the apical surface of urothelial umbrella cells, and whether there are other uroplakin-associated
cell surface proteins that may be related to the urotheliat 'glycocalyx' coating that has been
hypothesized to play a key role in several bladder diseases (Aim 3). Results from this Project will shed light on the structure, function and regulation of urothelial plaques, and will have major implications on the molecular etiology and pathogenesis of several important bladder diseases including interstitial cystitis, urinary tract infection and bladder cancer formation.
哺乳动物尿路上皮的顶端表面几乎完全被看起来坚硬的尿路上皮斑块覆盖,这些斑块由 16 nm 尿斑蛋白颗粒组成,这些颗粒以六边形堆积成二维晶体。高度纯化的尿路上皮斑块由四种主要尿斑蛋白 (UP) 组成,即尿斑蛋白 Ia (27 kDa)、Ib (28 kDa)、II (15 kDa) 和 III (47 kDa)。两个四跨膜蛋白成员 UPIa 和 UPIb 优先分别与两个单跨膜结构域的尿斑蛋白 II 和 III 相互作用,形成两个尿斑蛋白对
由 UPIa/II 和 UPIb/III 组成。在最后的资助期间,我们从基因上消除了编码尿斑蛋白 II 和 III 的小鼠基因。缺乏这两种主要尿路上皮分化产物的小鼠具有严重异常的尿路上皮,缺乏典型的伞细胞;有异常小的尿路上皮斑块;并患有膀胱输尿管反流、肾积水,在某些情况下甚至导致新生儿死亡。这些结果表明,尿斑蛋白是尿路上皮斑块的完整亚基,有助于渗透性屏障功能,并且尿路上皮缺陷可能在某些泌尿道疾病中发挥作用。然而,关于尿斑蛋白缺陷如何影响尿路上皮和膀胱的整体功能、尿斑蛋白如何与尿斑蛋白相互作用,人们知之甚少。
细胞质和其他膜相关蛋白,以及尿路病原细菌的尿斑蛋白受体的表面可及性。本项目拟议的研究将试图通过研究 uroptakin 基因的消融如何影响膀胱的通透屏障和排尿功能来回答其中一些问题(目标 1); uroplakins 如何与一些可能在介导 uroplakins 中发挥作用的细胞质蛋白相互作用:细胞骨架相互作用和信号转导(目标 2);尿路上皮伞细胞顶端表面上的尿斑蛋白分子的可及性,以及是否存在其他尿斑蛋白相关的分子
细胞表面蛋白可能与尿路上皮“糖萼”涂层有关,该涂层已被
假设在多种膀胱疾病中发挥关键作用(目标 3)。该项目的结果将揭示尿路上皮斑块的结构、功能和调节,并将对包括间质性膀胱炎、尿路感染和膀胱癌形成在内的几种重要膀胱疾病的分子病因学和发病机制产生重大影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Tung-Tien Sun其他文献
Tung-Tien Sun的其他文献
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{{ truncateString('Tung-Tien Sun', 18)}}的其他基金
Program Project: Growth Differentiation and Disease of Urothelium
计划项目:尿路上皮的生长分化和疾病
- 批准号:
8694872 - 财政年份:2014
- 资助金额:
$ 28.14万 - 项目类别:
CHAR OF GLYCANS FROM MOUSE & BOVINE UROPLAKINS IA & IB BY MASS SPECTROMETRY
来自小鼠的聚糖的字符
- 批准号:
7722979 - 财政年份:2008
- 资助金额:
$ 28.14万 - 项目类别:
CHAR OF GLYCANS FROM MOUSE & BOVINE UROPLAKINS IA & IB BY MASS SPECTROMETRY
来自小鼠的聚糖的字符
- 批准号:
7601973 - 财政年份:2007
- 资助金额:
$ 28.14万 - 项目类别:
Membrane Organisation by Tetraspanins and Small Multi-transmembrane
四跨膜蛋白和小型多跨膜的膜组织
- 批准号:
7162144 - 财政年份:2006
- 资助金额:
$ 28.14万 - 项目类别:
CHAR OF GLYCANS FROM MOUSE & BOVINE UROPLAKINS IA & IB BY MASS SPECTROMETRY
来自小鼠的聚糖的字符
- 批准号:
7369229 - 财政年份:2006
- 资助金额:
$ 28.14万 - 项目类别:
CHAR OF GLYCANS FROM MOUSE & BOVINE UROPLAKINS IA & IB BY MASS SPECTROMETRY
来自小鼠的聚糖的字符
- 批准号:
7182184 - 财政年份:2005
- 资助金额:
$ 28.14万 - 项目类别:
CHAR OF GLYCANS FROM MOUSE & BOVINE UROPLAKINS IA & IB BY MASS SPECTROMETRY
来自小鼠的聚糖的字符
- 批准号:
6978486 - 财政年份:2004
- 资助金额:
$ 28.14万 - 项目类别:
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