PATHOGENESIS OF DISEASE IN MUCOPOLYSACCHARIDOSIS I AND VII

粘多糖贮积症 I 和 VII 疾病的发病机制

• 批准号: 7729874
• 负责人: Katherine P. Ponder
• 金额: $ 39.66万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729874
• 关键词: Animal Model; Aorta; Aortic Diseases; Beta-glucuronidase; Biological Assay; Bone Marrow Transplantation; Canis familiaris; Cardiovascular system; Cartilage; Cathepsins; Cervical spine; Clinical; Collagen; Data; Development; Dilatation - action; Disease; Elastases; Elastin; Enzymes; Evaluation; Family; Future; Gene Expression; Genes; Glycosaminoglycans; Goals; Hematopoietic Stem Cell Transplantation; Histopathology; Intervertebral disc structure; Longevity; Lysosomal Storage Diseases; Lysosomes; Matrix Metalloproteinases; Mechanics; Modeling; Mucopolysaccharidoses; Mucopolysaccharidosis I; Mucopolysaccharidosis I S; Mucopolysaccharidosis V; Mucopolysaccharidosis VII; Mus; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Property; Protease Inhibitor; Proteins; Quality of life; RNA analysis; Role; Site; Symptoms; Testing; Tissues; Up-Regulation; Vertebral column; articular cartilage; bone; enzyme activity; enzyme replacement therapy; gene therapy; improved; matrix metalloproteinase 12; mouse model; nucleus pulposus; prevent; spine bone structure; vertebra body

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.

粘多糖样沉积症I（MPS I）和MPS VII是溶酶体贮积病， 由于β-利杜糖醛酸酶活性不足， 和β-葡萄糖醛酸酶。这导致多系统疾病 涉及主动脉和心脏、骨和关节、脑、肺和许多其它部位。 虽然现有的疗法已经减少了疾病的许多方面，但主动脉和血管壁的损伤仍然存在。 颈椎一直很难治疗。主动脉和脊柱都含有弹性蛋白， 胶原蛋白，这对它们的结构完整性非常重要。我们假设 降解这些蛋白质的蛋白酶的上调是一种常见的病理生理学改变， 导致主动脉和脊柱疾病的途径。主动脉经历弹性蛋白断裂， 进行性扩张，可能导致心血管功能不全， 手术我们以前已经证明主动脉疾病与上调 小鼠组织蛋白酶和基质金属蛋白酶家族的弹性蛋白酶 MPS I和MPS VII的型号。MPS中难以治疗的第二个部位是 颈椎，可能需要手术进行稳定。X光片显示 脊椎骨有破坏性的变化，我们的初步数据表明， 组织蛋白酶在椎间盘的纤维环中上调， 关节软骨目的本课题旨在进一步探讨该病的发病机制 在MPS VII犬的颈椎中，这将涉及结构研究， 脊柱的组织病理学此外，参与合成的基因的表达， 胶原蛋白和弹性蛋白的组装或破坏将在椎间融合器中进行评估。 MPS VII犬的椎间盘和终板软骨。的第二个目的 本项目将试图确定小鼠主动脉中特定蛋白酶的作用。 组织蛋白酶S和MMP-12在MPS I和MPS II组主动脉中均显著上调， MPS VII小鼠和犬。MPS VII小鼠将与组织蛋白酶S缺陷或 MMP-12缺陷小鼠，以及对主动脉扩张和弹性蛋白断裂的影响 将被评估。如果一个特定的基因似乎在弹性蛋白中起主要作用， 碎片化，未来的后续研究将测试药物的效果， 抑制这些蛋白酶。这些研究可能表明， MPS中主动脉和颈椎的疾病是由于共同的机制， 可以为这些难以治疗的部位确定治疗方法。