Mechanisms of Oxalobacter-Induced Enteric Oxalate Excretion
草酸杆菌诱导肠道草酸排泄的机制
基本信息
- 批准号:7649014
- 负责人:
- 金额:$ 33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-16 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:APPBP2 geneAddressAlanine-glyoxylate aminotransferaseAmericanAnaerobic BacteriaAnimalsAnionsAttentionBacteriaBody BurdenBudgetsCalcium OxalateCalculiCarbon DioxideCell CommunicationCellsCreatinineDepositionDiseaseDoseEnteralEquilibriumEventExcretory functionExhibitsFecesFutureGene FamilyGenesHereditary DiseaseHeterozygoteHumanHyperoxaluriaIn VitroIncidenceInheritedIntestinesKidneyKidney FailureKidney TransplantationKnock-outKnockout MiceLarge IntestineLiverMetabolic DiseasesMovementMucous MembraneMusOxalatesOxalobacterPatientsPatternPharmacological TreatmentPhenotypePhysiologicalPhysiologyPopulationPreparationPrimary HyperoxaluriaProteinsPumpRattusRenal clearance functionRisk FactorsRodentRoleShunt DeviceSignal Transduction PathwaySourceSubstrate SpecificityTechniquesTestingTimeTissuesTracerUrineWestern BlottingWild Type Mouseabsorptionalternative treatmentbaseeffective therapyenzyme deficiencymRNA Expressionmicroorganismmouse modeloxalosispublic health relevancetreatment strategyurinary
项目摘要
DESCRIPTION (provided by applicant): Hyperoxaluria is considered to be a major risk factor in calcium oxalate stone disease which occurs in about 12% of the American population and, apart from reducing dietary sources of oxalate, there is currently no pharmacological treatment available. More serious complications associated with hyperoxaluria and hyperoxalemia, such as renal failure, stones, and tissue deposits of oxalate (oxalosis) also occur in Primary Hyperoxaluria (PH), a progressive inherited metabolic disorder caused by a liver deficiency of the enzyme alanine-glyoxylate aminotransferase (AGT) which is cured only by a combined liver-kidney transplant. Clearly, alternative treatment options for the oxalate-associated diseases require attention and we are proposing to examine promoting intestinal elimination and degradation of oxalate as a way of reducing both hyperoxaluria and hyperoxalemia. Several key pieces of information from our recent studies of colonic oxalate transport in rats/mice have provided the direction for the studies proposed here. First, we have shown that, in addition to degrading dietary sources of oxalate, the substrate/oxalate-specific microorganism, Oxalobacter sp., which resides exclusively in the large intestine, can significantly lower urinary oxalate excretion by inducing colonic oxalate secretion/excretion. We also have compelling results indicating this anaerobic bacterium interacts with the transporting mucosa by producing a secretagogue that activates these beneficial changes in intestinal oxalate handling. Second, based upon our studies using wild type (WT) and knockout (KO) mice, we have identified two key anion exchangers, namely PAT1 (slc26a6) and DRA (slc26a3), that contribute significantly to the movements of oxalate in the intestine and we hypothesize that the changes in oxalate transport induced by Oxalobacter are dependent upon the expression and function of these transporters. Thus, we will examine intestinal and renal handling of oxalate in PAT1 and DRA single KO mice as well as in a PAT1/AGT double KO mouse model and WT mice colonized with Oxalobacter and compared to their appropriate non-colonized counterparts. An understanding of the mechanistic basis for bacterial cell modulation of intestinal oxalate handling is fundamental to future efforts in identifying which strains of bacteria and/or bacterial products will be effective in the treatment of Primary Hyperoxaluria and calcium oxalate stone disease. PUBLIC HEALTH RELEVANCE: The studies proposed address the mechanisms by which Oxalobacter colonization of the large intestine induces enteric oxalate elimination and lowers urinary oxalate excretion. In addition, these studies will evaluate whether Oxalobacter modulates the function of two known important oxalate transporters using knockout mouse models with targeted deletion of slc26a3 (DRA) and slc26a6 (PAT1). Especially important and relevant to the present application, however, is the recent availability of a PAT1/AGT double KO mouse model which affords us a unique opportunity to evaluate PAT1 function/activity in the setting of Primary Hyperoxaluria, type1 (PH1), with and without Oxalobacter colonization. Understanding oxalate handling in PH1 and the potential roles and interactions of PAT1 and Oxalobacter in modulating the excessive body burden of oxalate in this genetic disease are now possible.
描述(由申请人提供):高草酸尿症被认为是草酸钙结石病的主要危险因素,大约 12% 的美国人口患有草酸钙结石病,除了减少草酸盐的膳食来源外,目前还没有可用的药物治疗方法。原发性高草酸尿症 (PH) 也会发生与高草酸尿症和高草酸血症相关的更严重的并发症,例如肾功能衰竭、结石和草酸盐组织沉积(草酸盐中毒),原发性高草酸尿症 (PH) 是一种由肝脏缺乏丙氨酸-乙醛酸转氨酶引起的进行性遗传代谢性疾病(AGT)只能通过肝肾联合移植才能治愈。显然,草酸盐相关疾病的替代治疗方案需要引起重视,我们建议研究促进肠道消除和草酸盐降解,作为减少高草酸尿症和高草酸血症的一种方法。我们最近对大鼠/小鼠结肠草酸盐转运的研究中的几条关键信息为本文提出的研究提供了方向。首先,我们已经证明,除了降解膳食来源的草酸盐之外,仅存在于大肠中的底物/草酸盐特异性微生物草酸杆菌,可以通过诱导结肠草酸盐分泌/排泄来显着降低尿草酸盐排泄。我们还获得了令人信服的结果,表明这种厌氧细菌通过产生促分泌素来与运输粘膜相互作用,从而激活肠道草酸盐处理中的这些有益变化。其次,根据我们使用野生型 (WT) 和基因敲除 (KO) 小鼠的研究,我们确定了两种关键的阴离子交换剂,即 PAT1 (slc26a6) 和 DRA (slc26a3),它们对草酸盐在肠道中的移动有显着贡献,并且我们假设草酸杆菌诱导的草酸盐转运的变化取决于这些转运蛋白的表达和功能。因此,我们将检查 PAT1 和 DRA 单 KO 小鼠以及 PAT1/AGT 双 KO 小鼠模型和定植有草酸杆菌的 WT 小鼠中的肠道和肾脏对草酸盐的处理,并与相应的非定植小鼠进行比较。了解细菌细胞调节肠道草酸盐处理的机制基础对于未来确定哪些细菌菌株和/或细菌产物将有效治疗原发性高草酸尿症和草酸钙结石病至关重要。 公共健康相关性:所提出的研究探讨了草酸杆菌在大肠定植诱导肠道草酸盐消除并降低尿草酸盐排泄的机制。此外,这些研究将使用靶向删除 slc26a3 (DRA) 和 slc26a6 (PAT1) 的基因敲除小鼠模型来评估 Oxalobacter 是否调节两种已知的重要草酸转运蛋白的功能。然而,特别重要且与本申请相关的是最近推出的 PAT1/AGT 双 KO 小鼠模型,该模型为我们提供了一个独特的机会来评估原发性高草酸尿症 1 型 (PH1) 背景下的 PAT1 功能/活性,以及无草酸杆菌定植。现在可以了解 PH1 中的草酸盐处理以及 PAT1 和 Oxalobacter 在调节这种遗传性疾病中草酸盐过多的身体负担方面的潜在作用和相互作用。
项目成果
期刊论文数量(0)
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Marguerite Hatch其他文献
Marguerite Hatch的其他文献
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{{ truncateString('Marguerite Hatch', 18)}}的其他基金
An integrated, functional, molecular, and metabolomic approach to understand Oxalobacter-induced elimination of oxalate
一种了解草酸杆菌诱导的草酸盐消除的综合、功能、分子和代谢组学方法
- 批准号:
9514975 - 财政年份:2016
- 资助金额:
$ 33万 - 项目类别:
An integrated, functional, molecular, and metabolomic approach to understand Oxalobacter-induced elimination of oxalate
一种了解草酸杆菌诱导的草酸盐消除的综合、功能、分子和代谢组学方法
- 批准号:
9355627 - 财政年份:2016
- 资助金额:
$ 33万 - 项目类别:
An integrated, functional, molecular, and metabolomic approach to understand Oxalobacter-induced elimination of oxalate
一种了解草酸杆菌诱导的草酸盐消除的综合、功能、分子和代谢组学方法
- 批准号:
9176389 - 财政年份:2016
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to Treat Hyperoxaluria Associated with P
益生菌诱导消除草酸治疗与 P 相关的高草酸尿症
- 批准号:
7947955 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to treat Hyperoxaluria
益生菌诱导消除草酸盐治疗高草酸尿症
- 批准号:
8136624 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to treat Hyperoxaluria
益生菌诱导消除草酸治疗高草酸尿症
- 批准号:
8541006 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to treat Hyperoxaluria
益生菌诱导消除草酸盐治疗高草酸尿症
- 批准号:
8328707 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
An integrated, functional, molecular, and metabolomic approach to understand Oxalobacter-induced elimination of oxalate
一种了解草酸杆菌诱导的草酸盐消除的综合、功能、分子和代谢组学方法
- 批准号:
9136604 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
Oxalate Handling in PAT1 and DRA Knockout Mice
PAT1 和 DRA 敲除小鼠中的草酸盐处理
- 批准号:
8043914 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to treat Hyperoxaluria
益生菌诱导消除草酸盐治疗高草酸尿症
- 批准号:
8719418 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
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一种了解草酸杆菌诱导的草酸盐消除的综合、功能、分子和代谢组学方法
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$ 33万 - 项目类别:
An integrated, functional, molecular, and metabolomic approach to understand Oxalobacter-induced elimination of oxalate
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9355627 - 财政年份:2016
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An integrated, functional, molecular, and metabolomic approach to understand Oxalobacter-induced elimination of oxalate
一种了解草酸杆菌诱导的草酸盐消除的综合、功能、分子和代谢组学方法
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9176389 - 财政年份:2016
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to Treat Hyperoxaluria Associated with P
益生菌诱导消除草酸治疗与 P 相关的高草酸尿症
- 批准号:
7947955 - 财政年份:2010
- 资助金额:
$ 33万 - 项目类别:
Probiotic-Induced Elimination of Oxalate to treat Hyperoxaluria
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