CHARACTERIZATION OF 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 具有多种临床特征的储物障碍，包括新生儿 黄疸、癫痫、智力和运动发育迟缓以及早产 死亡 NPC患者在肝脏中储存了多种脂质， 包括胆固醇、葡糖神经酰胺、乳糖神经酰胺， 磷脂，包括鞘磷脂。 一种不正常的 神经节苷脂也存在于脑中。 虽然这些患者 以前被认为有胆固醇代谢缺陷，但事实并非如此。 显然，脂质组成的这些变化是由于 鞘磷脂代谢，现在很明显，这些脂质的变化， 胆固醇代谢的缺陷是由于胆固醇代谢的分子缺陷， 其依据不明。 培养的皮肤成纤维细胞显示出减少的 将外源性胆固醇转化为胆固醇的能力 低密度脂蛋白。 这是一个建议， 在临床上建立一群患有遗传病的猫， 在生化上和人类的NPC一样 最近发现了一个家猫家族， 有神经系统异常的婴儿在不到一岁时死亡。 大鼠肝组织脂质和脑组织神经节苷脂的检测 这些幼猫的组织结构与 NPC患者。 发现培养的皮肤成纤维细胞具有 几乎完全不能分解外源性胆固醇。 我们有 我从原来的家庭中获得了五只猫（母亲，3只雌性 兄弟姐妹和1名男性兄弟姐妹）。 育种试验表明， 这些猫中至少有3只是NPC携带者，包括雄性。 我们有 生产了10只受NPC影响的小猫。 我们建议扩大殖民地，让受影响的猫只可供其他 对胆固醇代谢缺陷感兴趣的研究小组， 脂质代谢紊乱，溶酶体贮积病， 神经元功能和促进治疗模式的研究 对于这些疾病。 这项提案的具体目标是：1）建立一个猫群 与人NPC的生化和形态等同物，2）提供 这些猫的研究人员有兴趣在这种遗传疾病和缺陷 在胆固醇代谢，3），以确定骨的有效性 骨髓移植作为治疗NPC感染的猫，和5） 确定降低胆固醇药物作为治疗的有效性 NPC影响猫。 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 5只受影响的小猫将作为未治疗小猫保留 治疗研究的对照。 三只受影响的小猫将接受 4周龄时进行骨髓移植。 五只受影响的小猫将 从4周龄开始喂食低胆固醇饮食。 九 受影响的小猫将被分成三组， 降低胆固醇的药物。 将比较所有给药猫 在生化、临床和形态学上与未经治疗的 对照

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.