STUDIES ON THE MECHANISM OF PATHOGENESIS OF THE MUCOPOLYSACCHARIDOSES

粘多糖沉积症是一组遗传性疾病 其特征在于糖胺聚糖（GAG）的代谢缺陷。 的 疾病通常与严重的神经功能障碍有关， 系统以及肝、脾、心、骨和其它组织。 本课题的研究目的是探讨肝纤维化的发病机制， 这些疾病的重点是大脑参与和智力迟钝。 我们采用比较的方法。 为此，我们研究了 组织中GAG、鞘脂和相关溶酶体酶的变化 不同类型的MPS患者，我们在 临床和超微结构发现。 我们的实验室贡献了 在理解化学病理学，特别是 MPS IH、MPS IS、MPS II、MPS III A和MPS III B的神经化学。 到 补充人类受试者的研究，药物（苏拉明）诱导的动物 已经开发了MPS模型，并且MPS I的犬模型（自然） （α-L-艾杜糖醛酸酶缺乏症）已得到充分表征。 中 试图扭转这种无法治愈的疾病造成的逐渐恶化， 代谢紊乱，5只患有MPS I的狗移植了来自 正常或杂合的同窝仔。 移植的骨髓提供了 受影响的狗与自我更新的细胞来源，产生酶 完成代谢过程所需的能量 移植后一年 对于这种神经退行性代谢， 因为我们发现了中央神经系统内的明显纠正性变化， 狗的神经系统

The mucopolysaccharidoses (MPS) are a group of hereditary diseases characterized by defective metabolism of glycosaminoglycans (GAGs). The disorders are usually associated with severe dysfunction of the nervous system as well as of liver, spleen, heart, bone, and other tissues. Objective of this project is the study of mechanism of pathogenesis of these diseases with emphasis on brain involvement and mental retardation. We are using a comparative approach. For this purpose we study the changes, in GAGs, sphingolipids, and pertinent lysosomal enzymes in tissues of patients with various types of MPS and we make correlation in terms of clinical and ultrastructural findings. Our laboratory contributed significantly in understanding the chemical pathology and in particular the neurochemistry of MPS IH, MPS IS, MPS II, MPS III A and MPS III B. To complement the studies with human subjects, a drug (suramin) induced animal model of MPS has been developed and a canine model, (natural), of MPS I (Alpha-L-iduronidase deficiency), has been fully characterized. In an attempt to reverse the progressive deterioration caused by this incurable metabolic disorder, five dogs with MPS I were transplanted with marrow from normal or heterozygous littermates. Transplanted bone marrow provides the affected dogs with self-renewing source of cells that produce the enzyme needed to complete the metabolic process. One year after transplantation the results are very encouraging for this neurodegenerative metabolic disorder because we found marked corrective changes within the central nervous system of the dogs.