FELINE MODEL OF NIEMANN-PICK TYPE C

C型尼曼-匹克病（NPC）是一种常染色体隐性遗传的溶酶体 胆积症：临床特征包括新生儿黄疸发作， 智力和运动发育迟缓以及过早死亡。患者 NPC在肝脏中储存各种脂质，包括胆固醇， 葡糖神经酰胺、乳糖神经酰胺和磷脂，包括 鞘磷脂神经节苷脂的异常模式存在于 个脑袋NPC以前被认为是由于鞘磷脂的缺陷 代谢;现在知道脂质储存是由代谢缺陷引起的。 胆固醇运输出溶酶体和高尔基体。这是一项建议 为了维持并继续表征NPC的优秀猫科动物模型， 也是目前唯一的大型动物模型这只猫的共同特征 脂质沉积障碍和人NPC包括临床神经学体征， 遗传方式，肝肿大，神经内脏储存，如 光学和电子显微镜，以及储存的生化分析 （未酯化的胆固醇、鞘磷脂、糖脂和神经节苷脂）。 体外培养的皮肤成纤维细胞对外源性蛋白的吸收能力受损 胆固醇伴未酯化胆固醇核周蓄积 通过菲律宾染色证实的与人类疾病相同。我们 在过去的6年里，已经生产了26只受NPC影响的小猫。我们建议 扩大殖民地，让其他研究小组也能接触到受影响的猫 对胆固醇代谢缺陷感兴趣。血脂紊乱 代谢、溶酶体贮积病、神经元功能障碍和 以促进对这些疾病的治疗模式的研究。我们 也建议继续描述这种疾病的特征。具体目标 该提案的主要内容是：l）维持一个NPC猫群， 与人类NPC相同，并将这些猫和组织提供给其他人 investigators. 2)在生物化学和形态学上 表征猫NPC在不同年龄，包括泌尿系统，3）继续 评估骨髓移植作为治疗的有效性，4） 确定低胆固醇饮食与胆固醇的有效性 降低药物作为治疗，和5）确定基因，这是负责 猫NPC将保留约12个杂合子， 增加繁殖群体的规模，并增加产量， 受影响的小猫受影响的小猫将继续他评估为非 处理的对照。两只受影响的小猫将接受骨髓 在1周龄时进行移植。四只受影响的小猫将被喂得很低 从出生后1-2周开始， 年龄猫胎将在不同年龄从子宫中取出， 进行生化评价（脂质和神经节苷脂分析）， 通过光学和电子显微镜观察形态学。我们将继续 收集所有小猫的DNA，以提高找到同源基因的机会。 NPC基因 这个殖民地的继续存在将提供一个 急需的生物工具来检查未来的治疗试验 包括基因和蛋白质替代疗法。

Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder: clinical features include neonatal jaundice seizures, delayed mental and motor development, and premature death. Patients with NPC store a variety of lipids in their liver, including cholesterol, glucosylceramide, lactosylceramide, and phospholipids including sphingomyelin. An abnormal pattern of gangliosides is present in the brain. NPC was previously thought to be due to a defect in sphingomyelin metabolism; it is now know that lipid storage results from a defect in cholesterol trafficking out of the lysosome and Golgi. This is a proposal to maintain and continue to characterize an excellent feline model of NPC, and the only large animal model available. Features common to this feline lipid storage disorder and human NPC include clinical neurological signs, mode of inheritance, hepatomegaly, neurovisceral storage as evidenced by light and electron microscopy, and biochemical analysis of storage (unesterified cholesterol, sphingomyelin, glycolipids, and gangliosides). Impaired ability of cultured skin fibroblasts to esterify exogenous cholesterol with perinuclear accumulation of unesterified cholesterol demonstrated by filipin staining is identical to the human disease. We have produced 26 NPC affected kittens in the last 6 years. We propose to expand the colony to make affected cats available to other research groups interested in defects of cholesterol metabolism. disorders of lipid metabolism, lysosomal storage diseases, disorders of neuronal function and to facilitate investigations of modes of therapy for these diseases. We also propose to continue to characterize this disorder. The specific aims of this proposal are to l) maintain a colony of NPC cats with a disorder identical to human NPC, and offer these cats and tissues to other investigators. 2) continue to biochemically and morphologically characterize feline NPC at various ages, including neonatally, 3) continue to evaluate effectiveness of bone marrow transplantation as therapy , 4) determine the effectiveness of low cholesterol diet with cholesterol lowering drugs as therapy, and 5) identify the gene which is responsible for feline NPC. Approximately 12 heterozygotes will be maintained to increase the size of the breeding colony, and to increase production of affected kittens. Affected kittens will be continue to he evaluated as non treated controls. Two affected kittens will receive bone marrow transplants at l week of age. Four affected kittens will be fed very low cholesterol diet and cholesterol lowering drugs beginning at 1-2 weeks of age. Fetal cats will be removed from the uterus at varying ages and evaluated biochemically (lipid and ganglioside analyses) and morphologically by light and electron microscopy. We will continue to collect DNA from all kittens to improve chances of finding the homologous gene for NPC. The continued existence of this colony will provide a critically needed biological tool to examine future therapeutic trials involving both gene and protein replacement therapies.