FELINE NIEMANN - PICK TYPE C

FELINE NIEMANN - 选择 C ​​型

• 批准号: 7391970
• 负责人: CHARLES H VITE
• 金额: $ 1.34万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391970
• 关键词: FELINE; NIEMANN; PICK; TYPE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The only colony of cats with Niemann-Pick type C disease (NPC) was moved to the School of Veterinary Medicine of the University of Pennsylvania from Colorado State University using support from the NCRR P40 grant. A point mutation in the NPC gene is responsible for clinical signs in cats. Genetic deficiency of the transmembrane NPC1 protein results in a neurovisceral cholesterol-glycosphingolipidosis, which is characterized by severe and progressive cognitive and motor deficits in addition to seizures and hepatosplenomegaly. The metabolic basis of this disease is not fully understood but deficiency in NPC1 protein results in the abnormal intracellular transport of endocytosed cholesterol, and in cellular swelling due to the storage of unesterified cholesterol and glycosphingolipids (lactosylceramide, glucosylceramide, and gangliosides) in lysosomes and late endosomes. The storage of gangliosides in neurons, specifically GM2 ganglioside, results in meganeurite formation and ectopic dendritogenesis on cortical pyramidal neurons and multipolar cells of the claustrum and amygdala. Neuropathology of the brain also includes Purkinje cell death, axonal spheroid formation of GABAergic neurons, demyelination, and neurofibrillary tangles composed of tau protein. Studies performed in the NPC cat were critical for identifying axonal spheroid formation in GABAergic neurons and the correlation of neuroaxonal dystrophy with neurological dysfunction. The feline model of NPC disease was also used to identify the late endosomal/lysosomal accumulation of GM2 and GM3 gangliosides and unesterified cholesterol as well as the association of GM2 storage with meganeurite formation and abnormal dendritogenesis. To examine the effect of glycosphingolipid storage on NPC disease, three NPC cats were previously treated with N-bultyldeoxynojirimycin (NB-DNJ), an inhibitor of all glucosylceramide-based glycosphinglipids including lactosylceramide and the gangliosides. NPC cats treated with NB-DNJ daily for 23 to 54 days showed a delay in the onset of intention tremor and ataxia, diminished Parvalbumin-positive axonal spheroids, increased numbers of Calbindin-positive Purkinje cells, a reduction in brain ganglioside accumulation, and an increase in life span. This study underscored the importance of glycosphingolipid storage on disease progression and was the first therapy to effectively ameliorate disease progression in any species with NPC disease. Studies are being performed to further define the progression of nervous system disease in the feline model NPC disease using neurological examination, electrodiagnostic testing, nuclear magnetic resonance imaging (NMR), biochemistry, and histopathology. Concurrent with these studies we are evaluating the efficacy of N-butyldeoxynojirimycin, the neurosteroid allopregnanolone, and the combination of allopregnanolone and N-butyldeoxynojirimycin, to treat nervous system disease in feline NPC. We hypothesize that the treatment of NPC cats with these drugs will delay the onset of signs of neurological dysfunction, improve electrodiagnostic and NMR abnormalities, increase lifespan, increase Purkinje cell survival, and decrease ganglioside storage in the brain.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。使用NCRR P40 Grant的支持，来自科罗拉多州立大学宾夕法尼亚大学的唯一猫cat氏菌（NPC）被转移到宾夕法尼亚大学的兽医学院。 NPC基因中的点突变负责猫的临床体征。跨膜NPC1蛋白的遗传缺乏会导致神经脱落胆固醇 - 糖脂胆脂质病，其特征是严重和进行性认知和运动缺陷，除了癫痫发作和肝肾上腺素瘤。该疾病的代谢基础尚不完全理解，但是NPC1蛋白的缺乏会导致内吞胆固醇的细胞插入异常转运，以及由于储存未酯化的胆固醇和糖磷脂胆脂的储存而导致的细胞肿胀导致细胞肿胀（乳糖层，乳糖糖酰胺，葡萄糖糖酰胺和凝集蛋白酶体）和依赖糖苷类体）。神经节苷脂在神经元中的储存，特别是GM2神经节苷脂，会导致层状形成和异位树突生成在皮质锥体神经元以及claustrum和杏仁核的多极细胞上。大脑的神经病理学还包括Purkinje细胞死亡，GABA能神经元的轴突球体形成，脱髓鞘和由Tau蛋白组成的神经纤维缠结。在NPC CAT中进行的研究对于鉴定GABA能神经元中的轴突球体形成以及神经司长症与神经功能障碍的相关性至关重要。 NPC疾病的猫科动物模型还用于鉴定GM2和GM3神经节苷脂和未酯化胆固醇的晚期内体/溶酶体积累，以及GM2储存与肠硫酸盐形成和异常树突生成的关联。为了检查糖磷脂脂储存对NPC疾病的影响，先前用Nbultyldeoxynojirimycin（NB-DNJ）治疗了三只NPC猫，这是所有基于葡萄糖酰胺类糖磷脂的抑制剂，这是所有基于葡萄糖酰胺的糖脂磷脂的抑制剂，包括乳糖糖酰胺，包括乳糖糖酰胺和分子蛋白酶。每天用NB-DNJ治疗的NPC猫持续23至54天，意图震颤和共济失调的发作延迟，白蛋白酶阳性轴突球体减少，钙蛋白阳性阳性purkinje细胞数量增加，脑神经胶的积累和寿命增加。这项研究强调了糖磷脂脂对疾病进展的重要性，并且是第一种有效缓解任何NPC疾病物种中疾病进展的疗法。 正在进行研究以进一步定义NPC疾病中神经系统疾病的进展，使用神经系统检查，电诊断测试，核磁共振成像（NMR），生物化学和组织病理学。与这些研究同时，我们正在评估N-丁基氧基诺霉素，神经类固醇丙啉酮的功效，以及在Feline NPC中治疗Allopregnanolone和Allopregnanolone和Alloprepregnanolone和Alloprepregnanolone和N-Butyldeoxynojirimycin的疗效。我们假设使用这些药物对NPC猫的治疗将延迟神经功能障碍的迹象，改善电诊断和NMR异常，增加寿命，增加Purkinje细胞存活，并减少大脑中的神经节蛋白储存。