Pathophysiology of Lysosomal Free Sialic Acid Storage Disorders

描述(由申请人提供)：这项提案的广泛、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)的病理生理学机制，以确定新的治疗方法。这些疾病是常染色体隐性遗传性神经退行性疾病，与进行性运动功能障碍、智力低下和最终过早死亡有关。增大的细胞质空泡充满了氨基糖唾液酸，定义了细胞的病理，并且描述了唾液酸通过溶酶体膜的运输的缺陷。遗传学研究已经确定，编码一种名为唾液酸的单一蛋白质的基因的几个突变是导致这种疾病的原因。然而，对唾液酸的功能和遗传改变的生理效应的了解是有限的。初步数据表明，唾液酸转运体是一种唾液酸转运体，存在于晚期内体/溶酶体亚细胞室。数据进一步表明，这些疾病的主要缺陷是运输活动的丧失。最近开发的这些疾病的动物模型是通过靶向破坏小鼠唾液酸基因而产生的，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唾液酸突变相关的病理基础上的特定分子机制。第一个目的是描述唾液酸缺乏小鼠的发育和病理特征。第二个目的是确定silain的丢失是否会导致通常含有silain的晚期内体/溶酶体小泡的生物发生或功能缺陷。第三个目的是确定唾液酸失表达是否会改变唾液酸糖蛋白或神经节苷脂的时间调节表达。在这些目标方面的进展将使人们更好地理解这种运输蛋白的正常功能，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.