A MODEL OF HUMAN GANGLIOSIDOSIS

溶酶体储存疾病包括一个描述良好的遗传性疾病子集 有溶酶体分解代谢缺陷的代谢紊乱。严重的， 进行性中枢神经系统(CNS)功能障碍最为明显 以及许多这些疾病的临床重大后果，包括 神经节苷脂。尽管已经了解了很多关于具体错误的信息 在与这些疾病相关的溶酶体生物化学中，潜在的 中枢神经系统功能障碍的致病机制仍很不清楚 明白了。特异性溶酶体酶揭示的早期研究进展 这些疾病的缺陷引发了人们的乐观情绪，即纠正疗法 可能会被开发出来。不幸的是，在以下方面取得的进展甚微 实施有希望的治疗策略。事实上，当前的 对基本致病事件的理解空白，对 开发治疗策略，因为尚不清楚中枢神经系统是否 在纠正溶酶体分解代谢后，功能将恢复。 该项目将开发具有良好特性的动物模型 神经节苷脂增多症探讨涉及发病机制和 溶酶体贮积性疾病的治疗。我们的研究表明 缺陷性脑损伤后突触膜成分的改变 猫神经节苷脂沉积症中神经节苷脂的分解代谢。我们假设 这些变化在功能上表现为突触传递的改变， 在钙依赖机制上有主要作用，在形态上 过量环磷酸腺苷诱导的神经细胞膜异常生长。我们的 拟议的研究将通过系统地研究这一令人兴奋的假说 猫神经元膜功能特性的研究 神经节苷脂。我们有理由对这种可能性持乐观态度 骨髓移植在溶酶体治疗中的应用 储藏疾病。然而，至关重要的是，全面的研究必须 在有效的实验动物模型中进行，这将严格测试 大鼠内脏器官和中枢神经系统的生化和形态变化 北京时间。因此，我们建议进行系统的研究，重点是 评价骨髓移植治疗溶酶体储存性疾病的效果 GM1神经节苷脂沉积症。

Lysosomal storage diseases comprise a well delineated subset of inherited metabolic disorders with defective lysosomal catabolism. Severe, progressive central nervous system (CNS) dysfunction is the most apparent and clinically significant consequence of many of these diseases, including the gangliosidoses. Although much has been learned about specific errors in lysosomal biochemistry associated with these diseases, the underlying pathogenetic mechanisms responsible for CNS dysfunction remain very poorly understood. Early progress in revealing specific lysosomal enzyme deficiencies in these diseases raised optimism that corrective therapy could be developed. Unfortunately, little progress has been made toward implementation of promising therapeutic strategies. In fact, the current void in understanding basic pathogenetic events impacts significantly on development of therapeutic strategies, since it is not known if CNS function will be restored following correction of lysosomal catabolism. This project will exploit well characterized animal models of the gangliosidoses to probe crucial questions involving pathogenesis and therapy of lysosomal storage diseases. Our studies demonstrate major alterations in synaptic membrane composition induced by defective ganglioside catabolism in feline Gm1 gangliosidosis. We hypothesize that these changes are manifested functionally by altered synaptic transmission, with major effects on Ca++ dependent mechanisms, and morphologically by aberrant neuronal membrane growth induced by excess cyclic AMP. Our proposed studies will pursue this exciting hypothesis by systematically exploring the functional properties of neuronal membrane in the feline gangliosidoses. There is some reason for optimism about the possible application of bone marrow transplantation (BMT) therapy for lysosomal storage diseases. However, it is crucial that comprehensive studies be performed in valid experimental animal models which will rigorously test biochemical and morphological changes in visceral organs and CNS following BMT. Therefore, we propose to perform systematic studies focused on evaluating BMT therapy for lysosomal storage diseases employing cats with Gm1 gangliosidosis.