Mechanism, modification, and intervention in a pre-clinical model of galactosemia

 描述(由申请人提供) 典型的半乳糖血症(CG)是一种潜在的致命性遗传病，由半乳糖-1P尿苷转移酶(GALT)的严重缺失引起；CG是美国新生儿筛查发现的第二种最常见的代谢疾病。尽管新生儿确诊并终身限制半乳糖饮食，这是目前的护理标准，但大多数受影响的儿童在成长过程中经历了一系列使人衰弱的认知、行为、运动、女性生殖和其他残疾。这些长期并发症的机制尚不清楚，阻碍了预后和更有效的治疗方法的开发。该项目的目标是确定与GALT缺乏症相关的急性和长期结果的机制(S)，并在临床前环境中利用这一知识来确定和测试CG的候选药物干预措施。为了实现这些目标，我们将采用模型系统和人类受试者相结合的方法。具体地说，我们将在GALT缺乏症的果蝇模型中进行系统水平的生化和遗传学研究，该模型既展示了发育中的急性半乳糖敏感性，也展示了半乳糖独立的成年运动、女性生育能力和与学习相关的行为表型，并使用患者样本进行有针对性的后续研究，以确保相关性。这一策略避开了有限患者数量的其他严重影响，使对机制的开放研究得以实现，这些机制需要了解CG急性和长期结果的基础。我们的具体目标包括：(1)确定果蝇和人类GALT缺乏症的代谢后果，(2)确定GALT缺乏症果蝇和患者急性和长期结果的遗传修饰物，以及(3)使用GALT缺失型果蝇CG模型测试候选的药理结果修饰物。这些研究的结果将揭示是什么导致了CG的急性和长期后遗症，并将为改善干预措施提供第一个循证步骤。

 DESCRIPTION (provided by applicant) Classic galactosemia (CG) is a potentially lethal genetic disease that results from profound loss of galactose-1P uridylyltransferase (GALT); CG is the second most common metabolic disorder identified by newborn screening in the US. Despite neonatal diagnosis and lifelong dietary restriction of galactose, which is the current standard of care, a majority of affected children grow to experience a constellation of debilitating cognitive, behavioral, movement, female reproductive, and other disabilities. The mechanisms that underlie these long-term complications remain unknown, hindering prognosis and the development of more effective treatments. The goals of this project are to define the mechanism(s) of acute and long-term outcomes associated with GALT deficiency and leverage that knowledge in a preclinical setting to identify and test candidate pharmacological interventions for CG. To achieve these goals we will apply a combined model system plus human subjects approach. Specifically, we will conduct systems-level biochemical and genetic studies in a Drosophila melanogaster model of GALT deficiency that demonstrates both acute galactose sensitivity in development and also galactose-independent adult movement, female fertility, and learning- related behavioral phenotypes, with targeted follow-up studies using patient samples to ensure relevance. This strategy circumvents the otherwise crippling effect of limited patient numbers to enable the open-minded studies of mechanism needed to understand the bases of acute and long-term outcomes in CG. Our Specific Aims include: (1) define the metabolomic consequences of GALT deficiency in both Drosophila and humans, (2) identify genetic modifiers of acute and long-term outcomes in GALT deficient Drosophila and patients, and (3) test candidate pharmacological modifiers of outcome using a GALT-null Drosophila model of CG. The results of these studies will reveal what causes the acute and long-term sequelae of CG and will provide a first evidence-based step toward improved intervention.