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: 7923965
• 负责人: Katherine P. Ponder
• 金额: $ 38.4万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923965
• 关键词: Animal Model; Animals; Aorta; Aortic Diseases; Beta-glucuronidase; Biological Assay; Bone Marrow Transplantation; Canis familiaris; Cardiovascular system; Cartilage; Cathepsins; Cervical spine; Clinical; Collagen; Connective Tissue; Data; Development; Dilatation - action; Disease; Elastases; Elastin; Enzymes; Family; Future; Gene Expression; Genes; Glycosaminoglycans; Goals; Hematopoietic Stem Cell Transplantation; Histopathology; Human; Intervertebral disc structure; L-Iduronidase; Longevity; Lysosomal Storage Diseases; Lysosomes; Matrix Metalloproteinases; Mechanics; Microarray Analysis; 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; Proteins; Quality of life; RNA; RNA analysis; Role; Site; Structure; Symptoms; Testing; Time; Tissues; Up-Regulation; Vertebral column; articular cartilage; bone; enzyme activity; enzyme replacement therapy; gene therapy; improved; inhibitor/antagonist; matrix metalloproteinase 12; mouse model; nucleus pulposus; prevent; sample collection; spine bone structure; transcription factor; 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I（MPS I）和MPS VII是溶酶体储存疾病 由于-氟唱酶的防御活性，哪种糖胺聚糖（GAG）积累 和-葡萄糖醛酸酶。这导致多系统疾病 涉及主动脉和心脏，骨骼和关节，大脑，肺以及许多其他部位。 尽管现有疗法减少了疾病，主动脉和疾病的许多方面 颈椎很难治疗。主动脉和脊柱都包含弹性蛋白， 胶原蛋白，这对于它们的结构完整性非常重要。我们假设这一点 降解这些蛋白质的蛋白质上调是一种常见的病理生理学 主动脉和脊柱疾病的途径。主动脉经历弹性蛋白碎片和 进行性扩张，这可能导致心血管功能不全，需要 外科手术。我们以前已经表明，主动脉疾病与上调有关 小鼠中组织蛋白酶和基质金属蛋白酶（MMP）家族的弹性酶的弹性酶 MPS I和MPS VII的模型。第二个难以在MP中治疗的站点是 颈椎，可能需要手术才能稳定。 X光片证明 椎骨具有破坏性的变化，我们的初步数据表明 在椎间盘的环纤维中，组织蛋白酶被上调 关节软骨。该项目的目标将进一步评估疾病的发病机理 在MPS VII犬的颈椎中，该犬将涉及结构研究和 脊柱的组织病理学。另外，与合成有关的基因的表达， 将评估胶原蛋白和弹性蛋白的装配或破坏 MPS VII狗中椎骨的椎间盘和末端软骨。第二个目标 该项目将尝试确定特定蛋白酶在主动脉中小鼠中的作用。 在MPS I和 国会议员VII小鼠和狗。 MPS VII小鼠将与组织蛋白酶缺陷或 MMP-12缺乏小鼠，以及对主动脉扩张和弹性蛋白片段的影响 将进行评估。如果特定基因似乎在弹性蛋白中起主要作用 破碎化，未来随后的研究将测试可以 抑制这些蛋白酶。这些研究可能表明 主动脉中的疾病和MPS中的颈椎是由于一种共同的机制，并且 可以确定这些难以治疗的地点的疗法。