A MODEL OF HUMAN GANGLIOSIDOSIS

溶酶体贮积病是一种遗传性代谢紊乱， 缺陷型溶酶体catalysis 重度，进行性中枢神经系统 神经系统（CNS）功能障碍是最明显的， 许多这些疾病的临床显著后果， 包括神经节苷脂增多症 尽管我们已经了解到 关于溶酶体生物化学的特定缺陷， 这些疾病的潜在发病机制 对中枢神经系统功能障碍的原因仍然知之甚少。 揭示特异性溶酶体酶缺乏症的早期进展 在这些疾病中，人们乐观地认为，矫正治疗可以 开发 不幸的是， 实施有前景的治疗策略。 实际上 目前缺乏对基本致病事件的了解 严重阻碍了治疗药物的开发 战略布局 该项目将利用良好的动物特性， 神经节苷脂沉积症的模型，以探讨关键问题， 溶酶体贮积病的发病机制和治疗。 我们 研究表明突触膜的主要变化 猫神经节苷脂催化剂缺陷引起的组合物 神经节苷脂沉积 我们假设这些变化 通过改变钙稳态导致钙的破坏， 依赖功能，包括神经传递。 我们提出的 研究将通过系统地研究这一令人兴奋的假设， 探索神经元膜的功能特性， 猫神经节苷脂沉积症。 我们有理由对 骨髓移植（BMT）的可能应用 用于溶酶体贮积病的治疗。 然而，至关重要的是 在有效的实验中进行全面的研究， 动物模型将严格测试生物化学和 骨髓移植后内脏器官和中枢神经系统的形态学变化。 因此，我们建议进行系统的研究，重点是 评估BMT治疗。 我们的假设是改变了的钙 内稳态是负责 这些疾病中的神经元功能障碍，第一次， 开发药物治疗的必要理由。

Lysosomal storage diseases are 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 disease, including the gangliosidoses. Although much has been learned about specific defects 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 significantly retards progress on development of therapeutic strategies. 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 gangliosidoses. We hypothesize that these changes are manifested by altered calcium homeostasis resulting in disruption of calcium- dependent functions, including neurotransmission. 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. Our hypothesis that altered calcium homeostasis is the central pathogenic effect responsible for neuronal dysfunction in these diseases provides, for the first time, the necessary rationale for development of drug therapy.