Genetic Linkages in Calcium Oxalate Stone Disease

描述（由申请人提供）：肾结石疾病是一种与重大疼痛、痛苦和经济成本相关的重大健康问题。5%至15%的人在70岁时会出现结石症状，其中至少50%的人会复发。迄今为止，唯一明确定义的导致高草酸尿和草酸钙结石病的遗传异常已被描述为原发性和继发性高草酸尿并与特定酶错误相关。然而，特发性草酸钙结石的家族性倾向，加上结石复发的共同趋势，导致人们猜测许多特发性草酸钙结石患者可能有遗传易感性。我们建议探索特发性高草酸钙结石病和草酸钙结石病之间的遗传联系，将目前用于探索高血压遗传基础的现有动物模型的方法和遗传观察应用于结石病。基因组方法在结石疾病中的应用是新的。拟议的研究将使我们能够定义介导特发性草酸钙结石病关键机制事件的遗传联系，包括高草酸尿、结晶尿和草酸钙晶体保留的开始、进展和生理后果。

DESCRIPTION (provided by applicant): Kidney stone disease is a substantial health problem associated with significant pain, suffering, and economic costs. 5% to 15% of the population will have a symptomatic episode of a stone by the age of 70 and at least 50% of these individuals will have recurrent disease. To date, the only well-defined genetic abnormalities leading to hyperoxaluria and calcium oxalate stone disease have been described for primary and secondary hyperoxaluria and associated with specific enzyme errors. However, the familial tendency of idiopathic calcium oxalate stone disease coupled with the common trend for stone recurrence have led to the speculation that many idiopathic calcium oxalate stone formers may have a genetic predisposition for their stone disease. We propose to explore the genetic linkages underlying idiopathic hyperoxaluria and calcium oxalate stone disease, utilizing and applying to stone disease the methods and genetic observations from existing animal models currently being used to explore the genetic basis of hypertension. The application of genomic methods to stone disease is new. The proposed studies will allow us to define the genetic linkages that mediate critical mechanistic events in idiopathic calcium oxalate stone disease including the initiation, progression, and physiologic consequences of hyperoxaluria, crystalluria, and calcium oxalate crystal retention. We will use available genomic rat resources to explore both the genetic linkages in calcium oxalate stone disease and the genetic linkages between calcium oxalate stone disease and hypertension. Three specific major breeding colonies will be used: 1) The Dahl SS rat that demonstrates salt sensitive hypertension, 2) A colony of Brown Norway rats that are about 62% consomic with the Dahl SS rat, and 3) Consomic strains of Dahl SS rats that have one chromosome at a time introgressed into the Dahl SS genetic background from the Brown Norway rat, creating a rat that is about 98% consomic with the parent Dahl rat. Our working hypothesis is that there are specific genetic linkages that are associated with idiopathic hyperoxaluria and calcium oxalate stone disease and that the pathophysiology of stone disease associated with hypertension is different from stone disease absent hypertension. There are three Specific Aims. Specific Aim I: To determine what the associative effect of hypertension and hyperoxaluria is on urine chemistry and how these associated challenges influence the potential for calcium oxalate stone disease. Specific Aim II: To define the specific tissue injury associated with hypertensive and with hyperoxaluric challenges and to correlate these findings with effective calcium oxalate crystal attachment and stone maturation. Specific Aim III: To identify the chromosomes that harbor genes that control major susceptibility and resistance to hyperoxaluria, calcium oxalate crystalluria, and stone disease using a chromosomal replacement panel of consomic Dahl SS rats.