Genetic Linkages in Calcium Oxalate Stone Disease

描述(由申请人提供)：肾结石是一种严重的健康问题，与巨大的疼痛、痛苦和经济成本有关。到70岁时，5%至15%的人口将出现结石的症状发作，其中至少50%的人将复发疾病。到目前为止，唯一明确的导致高草酸尿症和草酸钙结石病的基因异常被描述为原发性和继发性高草酸尿症，并与特定的酶错误有关。然而，特发性草酸钙结石病的家族性倾向以及结石复发的共同趋势导致了许多特发性草酸钙结石形成者可能有其结石疾病的遗传易感性的猜测。我们建议探索特发性高草酸尿症和草酸钙结石病背后的遗传联系，利用和应用现有动物模型的方法和遗传学观察来探索高血压的遗传基础。基因组学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确定在特发性草酸钙结石疾病中介导关键机械事件的遗传联系，包括高草酸尿、晶体尿和草酸钙晶体滞留的启动、进展和生理后果。 我们将利用现有的大鼠基因组资源来探索草酸钙结石疾病的遗传联系，以及草酸钙结石疾病和高血压之间的遗传联系。将使用三个特定的育种群体：1)表现出盐敏感型高血压的Dahl SS大鼠，2)与Dahl SS大鼠有约62%亲缘关系的棕色挪威大鼠群体，以及3)一次只有一条染色体的Dahl SS大鼠的共生体品系，从Brown挪威大鼠导入Dahl SS遗传背景，创造出与亲本Dahl大鼠约98%亲缘关系的大鼠。我们的工作假设是，特发性高草酸尿症和草酸钙结石病存在特定的遗传联系，与高血压相关的结石病的病理生理学不同于不伴高血压的结石病。有三个具体目标。 具体目标一：确定高血压和高草酸尿症对尿液化学的联合作用，以及这些相关挑战如何影响草酸钙结石的可能性。 具体目的II：明确高血压和高草酸刺激相关的特定组织损伤，并将这些发现与有效的草酸钙晶体附着和结石成熟相关联。 具体目的III：利用群体Dahl SS大鼠的染色体替换小组，鉴定含有控制对高草酸尿、草酸钙结晶尿和结石疾病的主要易感性和抵抗力的基因的染色体。

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.