Neuropathogenic Studies of Congenital Disorders of Glycosylation

先天性糖基化障碍（CDG）是一组神经代谢障碍，其特征在于： 高度保守的细胞糖基化机制中的遗传缺陷。大多数CDG患者 在PMM 2中有双等位基因突变，PMM 2是编码磷酸甘露变位酶2的基因， 活化甘露糖单糖用于N-连接的蛋白质糖基化。PMM 2-CDG患者患有 多系统受累，所有患者均患有神经损伤， 突出，进行性，并产生终身智力残疾，共济失调，往往癫痫发作。基于 CDG的遗传学基础，我们提出建立一种新的PMM 2-CDG小鼠模型，并对其进行鉴定 研究PMM 2在神经元和神经胶质细胞中的功能。我们还将调查 PMM 2在小脑发育和功能中的作用结合了基因、分子和 行为方法，我们希望不仅揭示新的见解CDG的致病机制， 而且还加速了基于机制的治疗方法的发展以改善治疗。此外，委员会认为， 我们拟议的研究将为广大研究界提供创新的工具和资源， 研究各种糖基化缺陷相关疾病的病理生理学。

Congenital disorders of glycosylation (CDG) are a group of neurometabolic disorders characterized by genetic defects in the highly conserved cellular glycosylation machinery. A majority of CDG patients have biallelic mutations in PMM2, a gene encoding the protein phosphomannomutase 2 required to activate mannose monosaccharides for N-linked protein glycosylation. PMM2-CDG patients suffer from multi-systemic involvement, and all patients uniformly suffer from neurological impairment that is prominent, progressive, and produces lifelong intellectual disability, ataxia and often seizures. Based on the genetic basis of CDG, we propose to establish and characterize a novel mouse model of PMM2-CDG to specifically investigate the function of PMM2 in neuronal and glial cells. We will also investigate the role of PMM2 in cerebellum development and function. With combined genetic, molecular, and behavioral approaches, we hope to not only reveal novel insight into the pathogenic mechanisms of CDG, but also to expedite the development of mechanism-based therapeutics to improve treatment. Moreover, our proposed study will provide the research community at large with innovative tools and resources to investigate the pathophysiology underlying a variety of glycosylation deficit-related disorders.