PATHOGENESIS OF DISEASE IN MUCOPOLYSACCHARIDOSIS I AND VII

粘多糖病I(MPS I)和MPS 7是一种溶酶体贮积性疾病 糖胺多聚糖(GAG)是由于-Liduronidase活性不足而积累的 和-葡萄糖醛酸苷酶。这导致了多系统疾病。 累及主动脉和心脏、骨骼和关节、脑、肺和许多其他部位。 尽管现有的治疗方法已经减少了疾病的许多方面，但主动脉和 颈椎一直很难治疗。大动脉和脊柱都含有弹性蛋白和 胶原蛋白，这是非常重要的结构完整性。我们假设 降解这些蛋白的蛋白水解酶的上调是一种常见的病理生理现象 大动脉和脊柱疾病的途径。大动脉经历弹性蛋白碎裂和 进行性扩张，可导致心血管功能不全，需要 做手术。我们先前已经证明，主动脉疾病与升压有关。 小鼠组织蛋白酶和基质金属蛋白酶家族中弹性酶的研究 MPS I和MPS VII的模型。在MPS中难以处理的第二个部位是 颈椎，可能需要手术才能稳定。放射照片显示 脊椎有破坏性的变化，我们的初步数据表明 组织蛋白酶在间盘的纤维环中上调，在 关节软骨。本项目的目标I将进一步评估疾病的发病机制。 在MPS VII犬的颈椎中，这将涉及结构研究和 脊椎的组织病理学。此外，参与合成的基因的表达， 将在椎间评估胶原和弹性蛋白的组装或破坏 MPS VII犬椎体的椎间盘和终板软骨。第二个目标是 该项目将试图确定特定的蛋白水解酶在小鼠主动脉中的作用。 组织蛋白酶S和基质金属蛋白酶-12在MPS I和MPS大鼠的主动脉中均明显上调。 MPS VII小鼠和狗。MPS VII小鼠将与组织蛋白酶S缺陷或 基质金属蛋白酶-12基因缺陷小鼠及其对主动脉扩张和弹性蛋白断裂的影响 将会被评估。如果某个特定基因似乎在弹性蛋白中起主要作用 碎裂，未来的后续研究将测试药物的效果， 抑制这些蛋白酶。这些研究可能会证明， MPS患者的主动脉和颈椎疾病是由共同的机制引起的，并且 可能会为这些难以治疗的部位找到一种治疗方法。

Mucopolysaccharidosis I (MPS I) and MPS VII are lysosomal storage diseases in which glycosaminoglycans (GAG) accumulate due to deficient activity in -Liduronidase and -glucuronidase, respectively. This results in multisystemic disease involving aorta and heart, bone and joints, brain, lung, and numerous other sites. Although existing therapies have reduced many aspects of disease, aorta and the cervical spine have been difficult to treat. Both aorta and spine contain elastin and collagen, which are very important for their structural integrity. We hypothesize that upregulation of proteases that degrade these proteins is a common pathophysiological pathway to disease in aorta and spine. Aortas undergo elastin fragmentation and progressive dilatation, which can result in cardiovascular insufficiency and require surgery. We have previously shown that aortic disease is associated with upregulation of elastases of the cathepsin and matrix metalloproteinase (MMP) families in mouse models of MPS I and MPS VII. A second site that is difficult to treat in MPS is the cervical spine, which can require surgery for stabilization. Radiographs demonstrate that vertebrae have destructive changes, and our preliminary data demonstrates that cathepsins are upregulated in the annulus fibrosus of the intervertebral disc and in articular cartilage. Aim I of this project will further evaluate the pathogenesis of disease in the cervical spine of MPS VII dogs, which will involve structural studies and histopathology of the spine. In addition, the expression of genes involved in synthesis, assembly, or destruction of collagen and elastin will be evaluated in the intervertebral disc and the endplate cartilage of the vertebrae in MPS VII dogs. The second aim of this project will attempt to determine the role of specific proteases in aorta in mice. Both cathepsin S and MMP-12 were markedly upregulated in the aorta of MPS I and MPS VII mice and dogs. MPS VII mice will be crossed with cathepsin S-deficient or MMP-12-deficient mice, and the effect upon aortic dilatation and elastin fragmentation will be evaluated. If a specific gene appears to play a major role in elastin fragmentation, subsequent studies in the future would test the effect of drugs that can inhibit these proteases. These studies may demonstrate that the development of disease in the aorta and the cervical spine in MPS is due to a common mechanism, and may identify a therapy for these difficult-to-treat sites.