FELINE MODEL OF NIEMANN-PICK TYPE C

C型尼曼-皮克病(NPC)是一种常染色体隐性遗传性溶酶体 包括新生儿在内的各种临床特征的储存障碍 黄疸、癫痫、智力和运动发育迟缓以及早产 死亡。鼻咽癌患者的肝脏中储存了各种脂类， 包括胆固醇、葡萄糖神经酰胺、乳糖神经酰胺和 包括鞘磷脂在内的磷脂。一种反常的模式 神经节苷脂也存在于大脑中。尽管这些患者是 以前被认为在胆固醇代谢方面有缺陷，但事实并非如此 很明显，这些脂质成分的变化是由于 鞘磷脂代谢，现在很明显，这些脂质的变化 成分是由于胆固醇代谢的缺陷，分子 其依据尚不清楚。培养的皮肤成纤维细胞显示减少 能够酯化呈现给胆固醇的外源胆固醇- 耗竭的细胞为低密度脂蛋白。这是一项旨在 建立一个患有遗传病的猫的临床群体，并 在生物化学上与人类的鼻咽癌相同。 最近发现了一个家猫家族，其中的小猫 神经异常在不到一岁时死亡。 大鼠肝脏脂质和脑组织神经节苷脂的检测 这些小猫显示的图案与在 人类鼻咽癌患者。培养的皮肤成纤维细胞被发现有 几乎完全不能酯化外源胆固醇。我们有 从原来的家庭中获得了5只猫(母亲，3只雌性 兄弟姐妹和1个男性兄弟姐妹)。育种试验证明，一种 这些猫中至少有3只是鼻咽癌携带者，包括雄性。我们有 生产了10只受鼻咽癌影响的小猫。 我们建议扩大猫群，使受影响的猫可供其他猫科动物使用 对胆固醇代谢缺陷感兴趣的研究小组， 脂代谢紊乱、溶酶体储存病、 神经功能和促进治疗模式的研究 治疗这些疾病。 这项提议的具体目标是：1)建立一个猫群 具有人类鼻咽癌的生化和形态等价物，2)提供 这些猫给了对这种遗传病和缺陷感兴趣的研究人员 在胆固醇代谢方面，3)测定骨骼的有效性 骨髓移植治疗鼻咽癌猫，以及5) 确定降胆固醇药物治疗高血压的有效性 受鼻咽癌影响的猫。将保留6个杂合子以增加 繁殖群体的大小，并增加受影响的产量 小猫。五只受影响的小猫将被视为未治疗 治疗研究的对照研究。三只受影响的小猫将收到 4周龄时进行骨髓移植。五只受影响的小猫将 从4周龄开始喂食极低胆固醇饮食。九 受影响的小猫将被分成3只一组，并给予3只不同的 降胆固醇药物。所有经过治疗的猫都将被比较 从生化、临床和形态上对未经治疗的 控制。

Niemann-Pick diseases type C (NPC) is an autosomal recessive lysosomal storage disorder with a variety of clinical features including 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 also present in the brain. Although these patients were previously thought to have a defect in cholesterol metabolism, it is not apparent that these changes in lipid composition are due to a defect in sphingomyelin metabolism, it is now apparent that these changes in lipid composition are due to defect in cholesterol metabolism, the molecular basis of which is unknown. Cultured skin fibroblasts show a decreased ability to esterify exogenous cholesterol presented to cholesterol- depleted cells as low density lipoprotein. This is a proposal to establish a colony of cats with a genetic disease clinically and biochemically identical to NPC in man. A family of domestic cats has recently been identified in which kittens have neurologic abnormalities died at less than one year of age. Examination of the lipids in liver and gangliosides in brain tissue of these kittens show a pattern identical to that found in tissues from human patients with NPC. Cultured skin fibroblasts are found to have near complete inability to esterify exogenous cholesterol. We have secured five cats from the original family (the mother, 3 female siblings and 1 male sibling). Breeding trials have established that a least 3 of these cats are carriers of NPC, including the male. We have produced 10 NPC affected kittens. 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. The specific aims of this proposal are to 1) establish a colony of cats with the biochemical and morphologic equivalent of human NPC, 2) provide these cats to researchers interested in this genetic disease and defects in cholesterol metabolism, 3) to determine the effectiveness of bone marrow transplantation as therapy for NPC affected cats, and 5) to determine the effectiveness of cholesterol lowering drugs as therapy for NPC affected cats. Six heterozygotes will be maintained to increase the size of the breeding colony, and to increase production of affected kittens. Five affected kittens will be maintained as non=treated controls for the therapy studies. Three affected kittens will receive bone marrow transplants at 4 weeks of age. Five affected kittens will be fed very low cholesterol diet beginning at 4 weeks of age. Nine affected kittens will be placed in groups of 3 and given 3 different cholesterol lowering drugs. All treated cats will be compared biochemically, clinically, and morphologically to their nontreated controls.