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性溶酶体 储存障碍：临床特征包括新生儿黄疸发作， 智力和运动发育迟缓，过早死亡。患有疾病的患者 NPC在他们的肝脏中储存各种脂类，包括胆固醇， 葡萄糖神经酰胺、乳糖神经酰胺和磷脂，包括 神经鞘磷脂。神经节苷脂的异常模式出现在 大脑。鼻咽癌之前被认为是由于鞘磷脂缺陷所致 新陈代谢；现在已经知道，脂肪储存是由于 胆固醇从溶酶体和高尔基体中流出。这是一项建议 为了保持并继续鉴定一个优秀的鼻咽癌猫科动物模型， 也是目前唯一可用的大型动物模型。这种猫科动物的共同特征 脂质储存障碍和人类鼻咽癌包括临床神经体征， 遗传方式、肝肿大、神经内脏储存 光学显微镜和电子显微镜，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)。 培养的皮肤成纤维细胞酯化外源的能力受损 胆固醇与未酯化胆固醇的核周积聚 经菲力平染色证实与人类疾病相同。我们 在过去的6年里，已经生产了26只鼻咽癌感染的小猫。我们建议 扩大群体，使受影响的猫可供其他研究小组使用 对胆固醇代谢缺陷感兴趣。脂代谢紊乱 代谢、溶酶体储存疾病、神经功能障碍和 以促进对这些疾病的治疗模式的研究。我们 还建议继续描述这种疾病的特征。具体目标 这项建议的一部分是为了L)维持一群患有疾病的鼻咽猫 与人类鼻咽癌完全相同，并将这些猫和组织提供给其他人 调查人员。2)继续在生化和形态上 描述不同年龄段的猫鼻咽癌的特征，包括新生儿，3)继续 评价骨髓移植的治疗效果，4) 确定含胆固醇的低胆固醇饮食的有效性 降低药物作为治疗方法，以及5)确定负责的基因 为了猫科鼻咽癌。大约12个杂合子将被维持到 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被评估为无 处理过的对照组。两只受影响的小猫将接受骨髓移植 L周龄时移栽。四只受影响的小猫将得到非常低的喂养 胆固醇饮食和降胆固醇药物从服用1-2周开始 年龄。胎猫将在不同的年龄和年龄被从子宫中取出 生物化学评估(脂质和神经节苷脂分析)和 通过光学和电子显微镜观察其形态。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 鼻咽癌的基因。这个殖民地的继续存在将提供一个 审查未来治疗试验急需的生物工具 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.