Pathophysiology of Lysosomal Free Sialic Acid Storage Disorders

描述（由申请方提供）：本提案的广泛、长期目标是确定溶酶体贮积症萨拉病和婴儿唾液酸贮积症（ISSD）的病理生理学相关机制，以确定新的治疗方法。这些疾病是常染色体隐性遗传的神经退行性疾病，与运动功能的进行性损害、精神发育迟滞和最终过早死亡相关。充满氨基糖唾液酸的扩大的细胞质空泡定义了细胞病理学，并且已经描述了唾液酸跨溶酶体膜转运的缺陷。遗传学研究已经确定，编码一种称为唾液酸蛋白的单一蛋白质的基因中的几个突变是致病的。然而，对唾液酸蛋白的功能和遗传改变的生理效应的理解是有限的。初步数据表明，唾液酸是一种唾液酸转运蛋白，存在于晚期内体/溶酶体亚细胞区室。数据进一步表明，这些疾病的主要缺陷是运输活动的损失。最近开发的这些疾病的动物模型已产生的小鼠唾液酸蛋白基因的靶向中断，但这些小鼠的表征是有限的。这三个具体的目标是针对确定特定的分子机制的病理学与唾液酸蛋白突变相关。第一个目的是描述唾液酸蛋白缺陷小鼠的发育和病理特征。第二个目的是确定唾液酸蛋白的缺失是否导致通常含有唾液酸蛋白的晚期内体/溶酶体囊泡的生物发生或功能缺陷。第三个目的是确定唾液酸蛋白的丧失是否改变唾液酸化糖蛋白或神经节苷脂的时间调节表达。这些目标的进展将导致更好地了解这种转运蛋白的正常功能，并深入了解这些疾病的病理生理学。

DESCRIPTION (provided by applicant): The broad, long-term goal of this proposal is to define mechanisms involved in the pathophysiology of the lysosomal storage disorders Salla disease and infantile sialic acid storage disorder (ISSD) in order to identify novel therapeutic approaches. These disorders are autosomal recessive neurodegenerative diseases associated with progressive impairment of motor function, mental retardation, and ultimately premature death. Enlarged cytoplasmic vacuoles filled with the amino sugar sialic acid define the cellular pathology and a defect in transport of sialic acid across lysosomal membranes has been described. Genetic studies have determined that several mutations in a gene encoding a single protein designated sialin are causative. However, the understanding of the function of sialin, and the physiological effect of genetic alterations is limited. Preliminary data indicate that sialin is a sialic acid transporter that resides in late- endosomal/lysosomal subcellular compartment. Data further indicate that the primary defect in these diseases is a loss of transport activity. A recently developed animal model for these disorders has been generated by the targeted disruption of the mouse sialin gene, but the characterization of these mice is limited. The three specific aims are directed at determining the specific molecular mechanisms underlying the pathology associated with mutations in sialin. The first aim is to describe the developmental and pathological features of sialin deficient mice. The second aim is to determine if loss of silain leads to a defect in the biogenesis or function of the late-endosomal/lysosomal vesicles that normally contain sialin. The third aim is to determine if loss of sialin alters the temporally regulated expression of sialylated glycoproteins or gangliosides. Progress in these aims will lead to an improved understanding of the normal function of this transport protein and insight into the pathophysiology of these diseases.