GALACTOCEREBROSIDASE DEFICIENCY IN THE DOG - MODEL OF KRABBE DISEASE IN HUMANS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。球形细胞白质营养不良症(GLD)或Krabbe病是一种常染色体隐性遗传性神经系统疾病，由溶酶体酶半乳糖脑苷酶(GALC)编码基因突变引起。GALC负责降解特定的半乳糖脂，包括几种在生产致密、稳定的髓鞘中起重要作用的半乳糖。未能充分降解半乳糖神经酰胺和神经鞘氨醇(半乳糖神经鞘氨醇)，导致在受GLD影响的人和动物的组织中观察到典型的病理结果。这些半乳糖磷脂通常是在活跃的髓鞘形成过程中合成的，而神经氨酸在GALC活性非常低的个体中积累。心磷脂对形成髓鞘的少突胶质细胞有很强的毒性，会导致它们死亡和尸检中发现的髓鞘稀少。虽然大多数人类患者在6个月前出现症状，并在18个月前死亡，但年龄较大的儿童和成年人也可以被诊断为GLD。目前唯一可用的治疗方法是异基因骨髓移植(BMT)。这种疾病有三个自然发生的动物模型，抽动鼠，凯恩和西高地白梗，以及恒河猴。人类、小鼠和猴子的GALC基因已经被克隆，并在杰斐逊大学医学院的大卫·温格博士的实验室中进行了表征。1996年报道克隆了凯恩和西高地白梗的该基因。繁育带菌犬群体由转诊中心与饲养员共同建立，并由RR02512维持。然而，这个群体后来被转移到温格·S博士的补助金下，并通过温格·S博士关于这种疾病的长期拨款的分包合同，一直维持在S兽医学校的动物护理设施中。转诊中心的工作人员为繁殖、诊断测试和儿科护理提供一些支持。

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. Globoid cell leukodystrophy (GLD) or Krabbe disease is an autosomal recessively inherited neurological disease caused by mutations in the gene coding for the lysosomal enzyme galacto-cerebrosidase (GALC). GALC is responsible for the degradation of specific galactolipids, including several that are important in the production of compact, stable myelin. A failure to adequately degrade galactosylceramide and psychosine (galactosylsphingosine) results in the characteristic pathological findings observed in tissue from humans and animals affected with GLD. These galactosphingolipids are normally synthesized during active myelination, and psychosine accumulates in individuals with very low GALC activity. Psychosine is highly toxic to the myelin-forming oligodendrocytes, causing their death and the paucity of myelin found on autopsy. While most human patients present with symptoms before six months of age and die before 18 months of age, older children and adults can also be diagnosed with GLD. The only treatment available at this time is heterologous bone marrow transplantation (BMT). This disease has three naturally occurring animal models, the twitcher mouse, the Cairn and West Highland White terriers, and the rhesus monkey. The human, mouse, and monkey GALC genes have been cloned and characterized in the laboratory of David Wenger, PhD, at the Jefferson University School of Medicine. Cloning of the gene in Cairn and West Highland White Terriers was reported in 1996. The colony of breeding carrier dogs was established by the Referral Center by working with breeders and was maintained RR02512. However, the colony was subsequently transferred to Dr. Wenger¿s grant and have been maintained within the Veterinary School¿s animal care facilities by a subcontract from Dr. Wenger¿s long-standing NIH grant on this disorder. Some support for breeding, diagnostic testing, and pediatric care is provided by the Referral Center personnel.