A MODEL OF HUMAN GANGLIOSIDOSIS

人类神经节细胞增多症模型

• 批准号: 3394368
• 负责人: HENRY J. BAKER
• 金额: $ 15.6万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3394368
• 关键词: Tay Sachs disease; adenosinetriphosphatase; autoradiography; axon; bone marrow transplantation; calcium; calcium transporting ATPase; calmodulin; cats; disease /disorder model; electrofocusing; electron microscopy; endoplasmic reticulum; gangliosidosis GM1; gel electrophoresis; histochemistry /cytochemistry; histopathology; homeostasis; inborn lysosomal enzyme disorder; ion transport; membrane proteins; membrane structure; mitochondria; model design /development; neural transmission; neurogenesis; neurotransmitters; nonhuman therapy evaluation; pathologic process; phosphorylation; protein kinase; sodium; synapses; synaptosomes; tissue /cell culture; tritium

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.

溶酶体贮积病是一种遗传性代谢紊乱疾病 溶酶体分解代谢有缺陷。 严重、进行性中枢性 神经系统（CNS）功能障碍是最明显且最严重的 许多这些疾病的临床显着后果， 包括神经节苷脂增多症。 虽然学到了很多东西 关于与相关的溶酶体生物化学的特定缺陷 这些疾病的发病机制 导致中枢神经系统功能障碍的原因仍然知之甚少。 揭示特定溶酶体酶缺陷的早期进展 在这些疾病中，人们乐观地认为纠正疗法可以 发达。 不幸的是，在这方面进展甚微 实施有前景的治疗策略。 事实上， 目前对基本发病事件的理解尚存空白 严重阻碍治疗药物开发的进展 策略。 该项目将利用特征良好的动物 神经节苷脂沉积症模型来探讨涉及的关键问题 溶酶体贮积病的发病机制和治疗。 我们的 研究表明突触膜发生重大变化 猫神经节苷脂分解代谢缺陷引起的成分 神经节苷脂沉积症。 我们假设这些变化已经显现出来 通过改变钙稳态，导致钙- 依赖功能，包括神经传递。 我们提出的 研究将通过系统地追求这一令人兴奋的假设 探索神经元膜的功能特性 猫神经节苷脂病。 有一些乐观的理由 骨髓移植（BMT）的可能应用 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化和 BMT 后内脏器官和 CNS 的形态变化。 因此，我们建议开展系统研究，重点关注 评估 BMT 治疗。 我们的假设改变了钙 稳态是负责的核心致病作用 这些疾病中的神经元功能障碍首次提供了 开发药物治疗的必要理由。