A MODEL OF HUMAN GANGLIOSIDOSIS

溶酶体储存疾病是一种遗传性代谢紊乱， 溶酶体分解代谢缺陷。严厉、进步的中央 神经系统(CNS)功能障碍是最明显和 其中许多疾病的临床重大后果， 包括神经节细胞增多症。尽管我们已经学到了很多东西 关于溶酶体生物化学中与 这些疾病，潜在的致病机制 对中枢神经系统功能障碍的责任仍然知之甚少。 特异性溶酶体酶缺乏症的早期研究进展 在这些疾病中提高了纠正治疗可能是 发展起来的。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， 当前在理解基本致病事件方面的空白 显著阻碍了治疗药物的开发进展 战略。该项目将开发具有良好特性的动物 神经节苷脂模型以探索涉及的关键问题 溶酶体贮积性疾病的发病机制及治疗。我们的 研究表明突触膜发生了重大变化 猫神经节苷脂分解代谢缺陷所致的合成 神经节苷脂。我们假设这些变化是显化的 通过钙稳态的改变导致钙的紊乱- 依赖功能，包括神经传递。我们的建议 研究将通过系统地研究这一令人兴奋的假说 大鼠神经元膜功能特性的研究 猫科神经节苷脂增多症。有一些理由对此持乐观态度 骨髓移植的可能应用 溶酶体贮积性疾病的治疗。然而，这是至关重要的 在有效的实验中进行全面的研究 动物模型将严格测试生化和 骨髓移植后内脏器官和中枢神经系统的形态变化。 因此，我们建议进行系统的研究，重点是 对骨髓移植治疗进行评估。我们的假说改变了钙 动态平衡是导致 这些疾病中的神经元功能障碍第一次提供了 发展药物疗法的必要理论基础。

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.