Pathophysiology of Lysosomal Free Sialic Acid Storage Disorders

描述（由申请人提供）：本提案的广泛、长期目标是确定溶酶体储存障碍Salla病和婴儿唾液酸储存障碍（ISSD）的病理生理机制，以确定新的治疗方法。这些疾病是常染色体隐性神经退行性疾病，与进行性运动功能损害、智力迟钝和最终过早死亡有关。细胞质中充满氨基酸糖唾液酸的增大液泡定义了细胞病理，并描述了唾液酸在溶酶体膜上运输的缺陷。遗传研究已经确定，编码一种称为sialin的单一蛋白质的基因中的几个突变是致病的。然而，对sialin的功能和基因改变的生理效应的理解是有限的。初步数据表明，唾液素是一种唾液酸转运蛋白，存在于内体/溶酶体亚细胞室中。数据进一步表明，这些疾病的主要缺陷是运输活动的丧失。最近开发了一种针对这些疾病的动物模型，该模型是通过靶向破坏小鼠sialin基因产生的，但这些小鼠的特征是有限的。这三个特定的目的是为了确定与sialin突变相关的病理的特定分子机制。第一个目的是描述唾液素缺乏小鼠的发育和病理特征。第二个目的是确定矽素的缺失是否会导致通常含有矽素的后内体/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素的丧失是否会改变唾液化糖蛋白或神经节苷的暂时调节表达。这些目标的进展将导致对这种转运蛋白正常功能的更好理解，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.