Role of Tamm-Horsfall Protein in Urinary Tract Defense
Tamm-Horsfall 蛋白在尿路防御中的作用
基本信息
- 批准号:7876617
- 负责人:
- 金额:$ 29.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-09-15 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmericanAntibodiesBladderCalciumCalcium OxalateCalculiClinicalCrystal FormationCrystallizationDNA Microarray ChipDefense MechanismsDiseaseDown-RegulationEnzymesEpithelialEpithelial CellsEscherichia coliEthylene GlycolsEvolutionExhibitsFunctional disorderFundingGene ExpressionGene Expression AlterationGene MutationGenesGoalsGrantHomeostasisHost DefenseHumanHyperoxaluriaHyperuricemiaImmunohistochemistryIn Situ HybridizationIn VitroInfective cystitisInjuryInterventionKidneyKidney CalculiKidney DiseasesKnock-outKnockout MiceLightLinkMicroarray AnalysisMolecularMusMutationNephrolithiasisNorthern BlottingOxalatesPathogenesisPhysiologic calcificationPhysiologyPlayProtein DeficiencyProteinsRenal functionResearch PersonnelReverse Transcriptase Polymerase Chain ReactionRoleRough endoplasmic reticulumSecondary toSeriesSeveritiesStagingSurfaceSusceptibility GeneSystemTestingTimeTransgenic MiceTubular formationUMOD geneUnited StatesUrate OxidaseUric AcidUrinary CalculiUrinary systemUrinary tractUrineUrologic DiseasesVascular calcificationWild Type Mousebasecalcificationdefense responseethylene glycolgene cloninghypercalciuriaimprovedin vitro activityin vivoinhibitor/antagonistinsightmacromoleculemajor urinary proteinsmutantosteopontinpreventprogramspromoterresearch studyresponseurinaryurolithiasis
项目摘要
DESCRIPTION (provided by applicant): The long-term goal of this project is to gain a better understanding of the molecular pathogenesis of urinary stone disease or urolithiasis. A centrally important function in maintaining urinary system homeostasis is to prevent supersaturated urine from forming crystals. Clearly a powerful set of defense mechanisms is required, but these mechanisms have been only partially characterized to date. During the last granting period, we have focused on in vivo roles of Tamm-Horsfall protein (THP, or uromodulin) in urinary tract defense. We found that inactivation of the THP gene predisposes mice to bladder colonization by transurethrally inoculated type 1-fimbriated E. coli. In addition, mice lacking THP develop spontaneous and chemically induced renal calcium crystals. The induction of renal crystals is accompanied by a marked increase in renal epithelial cells of osteopontin (OPN), a potent inhibitor of bone mineralization, vascular calcification and renal stone formation, raising the possibility that THP and OPN can act synergistically in inhibiting renal crystallization. In the next granting period, we will gain deeper insights into the role of THP as a critical innate defense factor in the urinary system by focusing on its role in preventing renal crystallization. First, we will examine whether THP knockout and THP mutation have different consequences on renal uric acid handling, by either inhibiting/inactivating uricase in THP knockout mice or by transgenically expressing human-relevant THP mutants in renal epithelial cells under the direction of the THP promoter. Second, we will examine whether the protective role of THP against renal crystallization is due directly to its modulation on renal calcium level or due indirectly to its protection against renal epithelial injury. Third, we will test the hypothesis that THP and OPN are co-inhibitors of renal calcification, by generating THP/OPN double knockouts and comparing the severity of renal calcification with that in the single knockouts. Finally, we will assess gene expression alterations in the renal epithelial cells in response to THP deficiency in order to better understand the roles of THP and other macromolecules in modulating renal crystallization and other renal functions. Results from these studies will shed new light on the molecular pathogenesis and intervention strategies for important urinary tract diseases such as urolithiasis, which afflicts millions of people annually in the United States alone.
描述(由申请人提供):本项目的长期目标是更好地了解泌尿系结石病或尿石症的分子发病机制。维持泌尿系统稳态的一个重要功能是防止过饱和尿液形成晶体。显然,需要一套强大的防御机制,但迄今为止,这些机制只得到了部分表征。在上一个授权期间,我们专注于Tamm-Horsfall蛋白(THP或尿调素)在尿路防御中的体内作用。我们发现THP基因的失活使小鼠易受经尿道接种的1型菌毛大肠杆菌的膀胱定植。杆菌此外,缺乏THP的小鼠产生自发性和化学诱导的肾钙结晶。肾结晶的诱导伴随着骨桥蛋白(OPN)的肾上皮细胞的显著增加,骨桥蛋白是骨矿化、血管钙化和肾结石形成的有效抑制剂,提高了THP和OPN可以协同作用抑制肾结晶的可能性。在下一个资助期,我们将通过关注THP在预防肾结晶中的作用,更深入地了解THP作为泌尿系统中关键的先天防御因子的作用。首先,我们将研究THP敲除和THP突变是否对肾脏尿酸处理有不同的后果,通过抑制/灭活THP敲除小鼠中的尿酸酶或通过在THP启动子的指导下在肾上皮细胞中转基因表达人类相关的THP突变体。其次,我们将研究THP对肾结晶的保护作用是直接由于其对肾钙水平的调节,还是间接由于其对肾上皮损伤的保护。第三,我们将通过产生THP/OPN双敲除并比较肾脏钙化的严重程度与单敲除中的严重程度来检验THP和OPN是肾脏钙化的共抑制剂的假设。最后,我们将评估THP缺乏时肾上皮细胞基因表达的改变,以更好地了解THP和其他大分子在调节肾结晶和其他肾功能中的作用。这些研究的结果将为重要的尿路疾病(如尿石症)的分子发病机制和干预策略提供新的线索,尿石症每年仅在美国就有数百万人受到影响。
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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{{ truncateString('XUE-RU WU', 18)}}的其他基金
BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Role of PPARg in theFormation and Progression of Carcinoma in situ of the Bladder
BCCMA:暴露于致癌物的退伍军人尿路上皮癌症发生的基本和转化机制:PPARg 在膀胱原位癌形成和进展中的作用
- 批准号:
10361590 - 财政年份:2022
- 资助金额:
$ 29.46万 - 项目类别:
BCCMA: Basic and Translational Mechanisms of Cancer Initiation of the Urothelium in Veterans Exposed to Carcinogens: Role of PPARg in theFormation and Progression of Carcinoma in situ of the Bladder
BCCMA:暴露于致癌物的退伍军人尿路上皮癌症发生的基本和转化机制:PPARg 在膀胱原位癌形成和进展中的作用
- 批准号:
10616472 - 财政年份:2022
- 资助金额:
$ 29.46万 - 项目类别:
Role of Tamm-Horsfall Protein in Urinary Tract Defense
Tamm-Horsfall 蛋白在尿路防御中的作用
- 批准号:
8785878 - 财政年份:2014
- 资助金额:
$ 29.46万 - 项目类别:
Molecular and Genetic Studies of Bladder Tumorigenesis
膀胱肿瘤发生的分子和遗传学研究
- 批准号:
10427138 - 财政年份:2013
- 资助金额:
$ 29.46万 - 项目类别:
Molecular and Genetic Studies of Bladder Tumorigenesis
膀胱肿瘤发生的分子和遗传学研究
- 批准号:
9257250 - 财政年份:2013
- 资助金额:
$ 29.46万 - 项目类别:
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