Bases of Pathophysiology in Galactosemia

描述(由申请人提供)：半乳糖-1-磷酸尿苷转移酶(GALT)的严重损伤导致被称为典型的半乳糖血症的先天性代谢错误。虽然这种疾病的急性和潜在的致命后遗症可以通过早期发现和终身限制饮食来解决或预防，但许多接受治疗的患者仍然会经历严重的长期并发症，包括近一半的患者出现认知障碍和言语/语言障碍，以及近85%的女性患者出现原发或过早的卵巢衰竭。尽管经过了50多年的研究，半乳糖血症的病理生理学机制仍然不清楚，这种疾病的动物模型也未能概括患者的表型，使研究进一步复杂化。我们提出的研究的长期目标是确定这种病理生理学的生化基础，从而能够开发出新的、更有效的治疗半乳糖血症的方法。我们的短期目标是确定特定的生化因素的作用，包括异常糖基化，作为半乳糖敏感性的潜在中介在半乳糖和/或大风受损的酵母和哺乳动物细胞中。我们进一步建议在一大群典型的半乳糖血症患者中测试这些候选因素作为潜在的预后介体的作用。我们的具体目标是：(1)确定Galk、Gale和UGP1作为半乳糖血症的酵母和人类细胞模型系统中半乳糖敏感性的候选修饰物的作用；(2)确定典型半乳糖症和泛发型半乳糖酶缺乏症患者成纤维细胞糖基化异常的性质和潜在原因(S)；以及(3)在典型半乳糖症患者队列中确定影响患者预后的生化修饰物。

DESCRIPTION (provided by applicant): Profound impairment of galactose-1-phosphate uridylyltransferase (GALT) results in the inborn error of metabolism known as classic galactosemia. Although the acute and potentially lethal sequelae of this disorder can be resolved or prevented by early detection and lifelong dietary restriction of galactose, many treated patients nevertheless go on to experience serious long-term complications, including cognitive disabilities and speech/language disorders in nearly half of all patients, and primary or premature ovarian failure in close to 85% of female patients. Despite more than 50 years of investigation, the mechanisms underlying the pathophysiology of galactosemia remain unclear, and animal models of the disease have failed to recapitulate the patient phenotype, further complicating studies. The long-term goal of our proposed research is to define the biochemical bases of this pathophysiology, thereby enabling development of novel and more effective treatments for patients with galactosemia. Our short-term objective is to define the roles of specific biochemical factors, including aberrant glycosylation, as potential mediators of galactose sensitivity in GALT- and/or GALE-impaired yeast and mammalian cells. We further propose to test the roles of these same candidate factors as potential mediators of outcome in a large cohort of patients with classic galactosemia. Our Specific Aims are: (1) to define the roles of GALK, GALE, and UGP1 as candidate modifiers of galactose sensitivity in yeast and human cell model systems of galactosemia, (2) to define the nature and underlying cause(s) of aberrant glycosylation in fibroblasts from patients with classic galactosemia and generalized epimerase-deficiency galactosemia, and (3) to define biochemical modifiers of patient outcomes in a cohort of classic galactosemia patients.