Bases of Pathophysiology in Galactosemia

描述（由申请方提供）：半乳糖-1-磷酸尿苷酰转移酶（GALT）的严重损伤导致称为典型半乳糖血症的先天性代谢缺陷。虽然这种疾病的急性和潜在致命的后遗症可以通过早期检测和终身半乳糖饮食限制来解决或预防，但许多治疗的患者仍然会经历严重的长期并发症，包括近一半患者的认知障碍和言语/语言障碍，以及近85%的女性患者的原发性或卵巢早衰。尽管有超过50年的研究，半乳糖血症的病理生理学的机制仍然不清楚，疾病的动物模型未能概括患者的表型，进一步复杂化的研究。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，从而为半乳糖血症患者开发新的更有效的治疗方法。我们的短期目标是确定特定的生化因素，包括异常的糖基化，作为潜在的半乳糖敏感性在GALT和/或GALE受损的酵母和哺乳动物细胞的介质的作用。我们进一步建议在一个大的经典半乳糖血症患者队列中测试这些相同的候选因素作为潜在的结局介质的作用。我们的具体目标是：（1）确定GALK、GALE和UGP 1作为半乳糖血症的酵母和人细胞模型系统中半乳糖敏感性的候选修饰剂的作用，（2）确定来自典型半乳糖血症和全身性差向异构酶缺乏性半乳糖血症患者的成纤维细胞中异常糖基化的性质和根本原因，和（3）在典型半乳糖血症患者队列中定义患者结果的生化修饰物。

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.