Oxalate handling and Oxalobacter formigenes colonization in a mouse model

描述（由申请人提供）：肾结石是一个主要的公共卫生问题，原因很大程度上未知。在美国，每年因泌尿系统结石诊断、治疗、疼痛管理和工资损失而产生的社会总成本超过20亿美元。肾结石患者中草酸钙含量超过50%的患者约占所有肾结石病例的75%。降低肾结石形成风险的一个重要策略是减少尿液中草酸盐的量。尿草酸盐来自内源性和饮食来源。目前还没有已知的方法来减少大多数患者的内源性草酸盐合成。因此，减少膳食草酸盐吸收的策略是一种有吸引力的替代方案。最近的研究表明，缺乏Oxalciformigenes（OxF）定植是结石形成的危险因素。此外，初步研究表明，对原发性高草酸尿症患者口服OxF可能会减少草酸盐排泄。然而，OxF定植改变肠道环境、影响尿草酸盐和肾结石形成的确切机制、其在人类中的自然史以及控制其持久性、人口密度和分布的因素仍然没有明确阐明。动物模型的发展将有助于我们对其中许多领域的理解。利用小鼠的优点包括易于操作和控制环境和饮食因素，以及便于研究特定基因影响的遗传修饰能力。我们已经表明，小鼠很容易殖民与管理OxF和保持殖民低草酸盐饮食。该提案旨在使用OxF定殖的小鼠模型来增强我们对饮食对草酸盐处理和OxF生物学和生长的影响的理解。最近发布的注释基因组序列的OxF将首次允许使用分子方法来回答有关OxF的生理和主机相互作用的令人信服的问题。该模型还将允许检查饮食草酸盐和钙对OxF以外的肠道细菌群体的潜在影响。如果特定的目标是成功地完成，他们将提供有价值的信息OxF生物学，OxF定植的重要因素，肠道分泌的草酸盐稳态的作用，草酸盐代谢中的其他草酸盐降解细菌的作用，并可能确定新的方式修改肠道环境和结石的风险。

DESCRIPTION (provided by applicant): Nephrolithiasis is a major public health problem of largely unknown cause. In the United States, total societal costs arising from urinary stone diagnosis, treatment, pain management, and lost wages total more than $2 billion annually. Kidney stones that contain more than 50% calcium oxalate account for approximately 75% of all kidney stone cases. An important strategy for reducing the risk of kidney stone formation is to decrease the amount of oxalate in urine. Urinary oxalate is derived about equally from both endogenous and dietary sources. There are currently no known means of decreasing endogenous oxalate synthesis in the majority of those afflicted. Thus, strategies to reduce dietary oxalate absorption represent an attractive alternative. Recent studies have indicated that a lack of Oxalobacter formigenes (OxF) colonization is a risk factor for stone formation. In addition, preliminary studies suggest that administering oral doses of OxF to patients with primary hyperoxaluria may decrease oxalate excretion. However, the precise mechanisms by which OxF colonization modifies the gut milieu, affects urinary oxalate and kidney stone formation, its natural history in humans, and the factors governing its persistence, population density and distribution have still not been clearly elucidated. The development of an animal model would facilitate our understanding of many of these areas. The utilization of mice has advantages including easy manipulation and control of environmental and dietary factors, and the ability for genetic modification which facilitates the study of the impact of specific genes. We have shown mice are readily colonized with administered OxF and retain colonization on low oxalate diets. This proposal aims to use a mouse model of OxF colonization to enhance our understanding of the impact of diet on oxalate handling and OxF biology and growth. The recent release of the annotated genomic sequence of OxF will for the first time permit the use of molecular approaches to answer compelling questions related to OxF physiology and host interactions. The model will also allow the potential effect of dietary oxalate and calcium on populations of gut bacteria other than OxF to be examined. If the specific aims are successfully completed they will provide valuable information about OxF biology, the factors that are important for OxF colonization, the role of enteric secretion in oxalate homeostasis, the role of other oxalate degrading bacteria in oxalate metabolism, and may identify new ways of modifying the gut milieu and stone risk.