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，大部分原因未知。在美国，尿路结石的诊断、治疗、疼痛管理和工资损失每年产生的社会总成本超过20亿美元。含有超过50%草酸钙的肾结石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含量。尿草酸盐的内源性和膳食来源大致相同。目前还没有已知的方法可以减少大多数患者的内源性草酸盐合成。因此，减少饮食中草酸盐吸收的策略是一个有吸引力的选择。最近的研究表明，缺乏formigenes草酸杆菌（OxF）定植是结石形成的危险因素。此外，初步研究表明，给予原发性高草酸尿患者口服剂量的OxF可能会减少草酸盐的排泄。然而，OxF定殖改变肠道环境，影响尿草酸盐和肾结石形成的确切机制，其在人类中的自然历史，以及控制其持久性，种群密度和分布的因素仍未明确阐明。动物模型的发展将促进我们对这些领域的理解。利用小鼠具有易于操纵和控制环境和饮食因素以及易于进行基因修饰的优点，便于研究特定基因的影响。我们已经证明小鼠很容易在给予OxF的情况下定植，并在低草酸饮食中保持定植。本研究旨在利用小鼠OxF定植模型来加深我们对饮食对草酸处理和OxF生物学和生长的影响的理解。最近发布的带注释的OxF基因组序列将首次允许使用分子方法来回答与OxF生理学和宿主相互作用相关的令人信服的问题。该模型还将允许研究草酸盐和钙对肠道细菌种群的潜在影响，而不是OxF。如果特定目标成功完成，它们将提供有关OxF生物学、OxF定植的重要因素、肠道分泌在草酸体内平衡中的作用、其他草酸降解细菌在草酸代谢中的作用等有价值的信息，并可能确定改变肠道环境和结石风险的新方法。

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.