PATHOGENESIS OF DISEASE IN MUCOPOLYSACCHARIDOSIS I AND VII
粘多糖贮积症 I 和 VII 疾病的发病机制
基本信息
- 批准号:7923965
- 负责人:
- 金额:$ 38.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Animal ModelAnimalsAortaAortic DiseasesBeta-glucuronidaseBiological AssayBone Marrow TransplantationCanis familiarisCardiovascular systemCartilageCathepsinsCervical spineClinicalCollagenConnective TissueDataDevelopmentDilatation - actionDiseaseElastasesElastinEnzymesFamilyFutureGene ExpressionGenesGlycosaminoglycansGoalsHematopoietic Stem Cell TransplantationHistopathologyHumanIntervertebral disc structureL-IduronidaseLongevityLysosomal Storage DiseasesLysosomesMatrix MetalloproteinasesMechanicsMicroarray AnalysisModelingMucopolysaccharidosesMucopolysaccharidosis IMucopolysaccharidosis I SMucopolysaccharidosis VMucopolysaccharidosis VIIMusOperative Surgical ProceduresOrganPathogenesisPathway interactionsPatientsPeptide HydrolasesPharmaceutical PreparationsPlayPropertyProteinsQuality of lifeRNARNA analysisRoleSiteStructureSymptomsTestingTimeTissuesUp-RegulationVertebral columnarticular cartilageboneenzyme activityenzyme replacement therapygene therapyimprovedinhibitor/antagonistmatrix metalloproteinase 12mouse modelnucleus pulposuspreventsample collectionspine bone structuretranscription factorvertebra body
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Katherine P. Ponder其他文献
859. Cats Produce a CTL Response That Reduces Expression of Human Factor IX and Human Factor VIII after Neonatal Gene Transfer and Represent an Important Model for Translation into Humans
- DOI:
10.1016/j.ymthe.2006.08.945 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Lingfei Xu;Manxue Mei;Mark E. Haskins;Patty O'Donnell;Karyn Cullen;Katherine P. Ponder - 通讯作者:
Katherine P. Ponder
73. Cats Produce a Potent CTL Response after Neonatal Gene Therapy That Can Be Blocked with CTLA4-Ig
- DOI:
10.1016/j.ymthe.2006.08.090 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Katherine P. Ponder;Baomei Wang;Ping Wang;Xiucui Ma;Ramin Herati;Bin Wang;Karyn Cullen;Patty O'Donnell;Tina M. Primeau;Mark E. Haskins - 通讯作者:
Mark E. Haskins
403. Long-Term, High alpha-L-iduronidase Expression in MPS I Dogs Following Neonatal, Intravenous, Retroviral Vector Gene Therapy
- DOI:
10.1016/j.ymthe.2006.08.466 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Anne Traas;Ping Wang;Xiucui Ma;Patricia O'Donnell;Meg Sleeper;Gus Aguirre;Mark Haskins;Katherine P. Ponder - 通讯作者:
Katherine P. Ponder
Effects of neonatal enzyme replacement therapy and simvastatin treatment on cervical spine disease in mucopolysaccharidosis type I dogs
- DOI:
10.1016/j.ymgme.2013.12.244 - 发表时间:
2014-02-01 - 期刊:
- 影响因子:
- 作者:
Lachlan J. Smith;Joseph A. Chiaro;Patricia O'Donnell;Neil R. Malhotra;Eileen M. Shore;Katherine P. Ponder;Mark E. Haskins - 通讯作者:
Mark E. Haskins
984. Liver Restricted Expression of Canine Iduronidase Does Not Prevent a CTL Response in Adult MPS I Mice after Retroviral Vector-Mediated Gene Therapy, but Transient Immunomodulation with CTLA4-Ig Combined with Anti-CD4 or Anti- CD40 Ligand Does
- DOI:
10.1016/j.ymthe.2006.08.1077 - 发表时间:
2006-01-01 - 期刊:
- 影响因子:
- 作者:
Xiucui Ma;Ramin Herati;Yuli Liu;Anne K. Hennig;Attila Kovacs;Katherine P. Ponder - 通讯作者:
Katherine P. Ponder
Katherine P. Ponder的其他文献
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{{ truncateString('Katherine P. Ponder', 18)}}的其他基金
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 - 财政年份:2009
- 资助金额:
$ 38.4万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
8245107 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
Retroviral Vector-mediated Liver Gene Therapy for MPS I
逆转录病毒载体介导的 MPS I 肝脏基因治疗
- 批准号:
6801420 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
7752811 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
7581492 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
Retroviral Vector-mediated Liver Gene Therapy for MPS I
逆转录病毒载体介导的 MPS I 肝脏基因治疗
- 批准号:
6813222 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
7623653 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
RETROVIRAL VECTOR-MEDIATED LIVER GENE THERAPY FOR MPS I
逆转录病毒载体介导的 MPS I 肝基因治疗
- 批准号:
8462966 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
Retroviral Vector-Mediated Liver Gene Therapy for MPS I
逆转录病毒载体介导的 MPS I 肝脏基因治疗
- 批准号:
7446367 - 财政年份:2003
- 资助金额:
$ 38.4万 - 项目类别:
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