A MODEL OF HUMAN GANGLIOSIDOSIS

溶酶体贮积病包括一个明确的遗传性疾病亚组， 代谢紊乱伴溶酶体催化剂缺陷。 严重， 进行性中枢神经系统（CNS）功能障碍是最明显的 和临床上显著的后果，包括 神经节苷脂沉积症 尽管我们已经了解了很多关于特定错误的信息， 在与这些疾病相关的溶酶体生物化学中， 导致中枢神经系统功能障碍的发病机制仍然很差 明白 特异性溶酶体酶研究的早期进展 这些疾病的缺陷使人们乐观地认为， 可以开发。 不幸的是， 实施有前景的治疗策略。 其实现在的 缺乏对基本致病事件的理解， 开发治疗策略，因为尚不清楚CNS是否 功能将在溶酶体catalysis的纠正后恢复。 该项目将利用良好表征的动物模型， 神经节苷脂中毒，以探讨涉及发病机制的关键问题， 溶酶体贮积病的治疗。 我们的研究表明， 缺陷引起的突触膜组成的改变 猫Gm1神经节苷脂沉积症的神经节苷脂代谢 我们假设 这些变化在功能上表现为突触传递的改变， 对Ca ++依赖性机制有主要影响， 异常的神经元膜生长诱导的过量环AMP。 我们 拟议的研究将系统地探讨这一令人兴奋的假设 探索猫神经元膜的功能特性 神经节苷脂沉积 有一些理由对可能发生的事情感到乐观。 骨髓移植（BMT）治疗溶酶体的应用 贮藏病害 然而，至关重要的是， 在有效的实验动物模型中进行， 内脏器官和中枢神经系统的生化和形态学变化 BMT。 因此，我们建议进行系统的研究，重点是 评估BMT治疗溶酶体贮积病的猫， 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.