Pathogenesis and Treatment of Bone Disease in the Mucopolysaccharidoses
粘多糖症骨病的发病机制及治疗
基本信息
- 批准号:10171788
- 负责人:
- 金额:$ 34.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAgeAnimal ModelBeta-glucuronidaseBindingBiological AssayBirthBone DiseasesBypassCanis familiarisCartilageCell physiologyCellsChondrocytesChondroitin SulfatesClinicalDeformityDermatan SulfateDevelopmentDiseaseDisease ProgressionDistributional ActivityDoseEnzymesExhibitsFailureFunctional disorderGlycosaminoglycansGrowthGrowth FactorHeparitin SulfateHumanHypertrophyImpairmentJointsLaboratoriesLesionLigandsLinkLithiumLithium CarbonateModelingMolecularMucopolysaccharidosesMucopolysaccharidosis VIIOsteogenesisParalysedPathogenesisPathologicPathway interactionsPatientsPhenotypePhysiologic OssificationRoleSignal PathwaySignal TransductionStressTherapeuticTissuesVertebral BoneWorkbeta cateninbonecartilaginouschronic painclinically relevanteffective therapyendoplasmic reticulum stressenzyme replacement therapyextracellularfamily geneticsimprovedin vivolong boneosteoblast differentiationosteogenicpostnatalpostnatal developmentskeletalskeletal abnormalityskeletal disorderspatial relationshipspinal cord compressionspine bone structuretherapeutic targettranscriptome sequencing
项目摘要
Abstract
The mucopolysaccharidoses (MPS) are a family of genetic, lysosomal storage disorders characterized by
deficiencies in enzymes that degrade glycosaminoglycans (GAGs). Patients with MPS suffer from crippling
skeletal abnormalities that are unresponsive to current treatments. MPS VII presents with a particularly severe
skeletal phenotype, where patients exhibit progressive kyphoscoliotic deformity and spinal cord compression
resulting in chronic pain and paralysis. MPS VII is caused by deficient beta-glucuronidase activity, leading to
accumulation of multiple GAG types. The molecular mechanisms linking this GAG accumulation to cellular
dysfunction and skeletal disease are poorly understood, impeding development of effective therapies. Our
laboratory uses a clinically-relevant, naturally-occurring canine model of MPS VII that closely mimics the
progression of skeletal disease that occurs in human patients. In previous work we demonstrated that MPS VII
dogs have cartilaginous lesions in the vertebrae that compromise the stability of the intervertebral joint. These
lesions are caused by failed conversion of cartilage to bone during postnatal growth. In preliminary studies, we
have identified the precise developmental window when abnormal ossification first manifests in MPS VII dogs
and that this can be traced to a failure of resident chondrocytes to progress through hypertrophic maturation.
We have also shown that there is abnormal GAG accumulation in MPS VII epiphyseal cartilage from an early
age, and, using whole transcriptome sequencing, that there is dysregulation of the Wnt/β-catenin signaling
pathway at this crucial juncture in the disease progression. Wnt growth factors are critical regulators of
chondrocyte differentiation, and GAGs are known to be important regulators of Wnt distribution and activity,
suggesting a link between GAG accumulation and dysregulation of this pathway. The objectives of this
proposal are to investigate mechanisms of failed bone formation in MPS VII and establish improved
treatment paradigms using a clinically-relevant canine model. Our central hypothesis is that abnormal
accumulation of GAGs in MPS VII epiphyseal cartilage disrupts the signaling pathways necessary to
initiate and sustain chondrocyte hypertrophic differentiation. Further, we hypothesize that to
effectively treat bone disease in MPS VII, it will be necessary to both normalize GAG turnover and
activate requisite osteogenic signaling pathways in epiphyseal cartilage. In Aim 1 we will define temporal
and spatial relationships between GAG accumulation and epiphyseal chondrocyte differentiation potential at
key stages of bone disease progression in MPS VII dogs, from birth to skeletal maturity. In Aim 2 we will
establish the critical role of Wnt/β-catenin signaling dysregulation in delayed epiphyseal bone formation in MPS
VII dogs. In Aim 3 we will establish if therapeutic targeting of Wnt/β-catenin signaling, alone and in combination
with enzyme replacement therapy, can enhance bone formation in MPS VII dogs.
摘要
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bone Remodeling and Disc Morphology in the Distal Unfused Spine After Spinal Fusion in Adolescent Idiopathic Scoliosis.
青少年特发性脊柱侧凸脊柱融合后远端未融合脊柱的骨重塑和椎间盘形态。
- DOI:10.1016/j.jspd.2018.12.004
- 发表时间:2019
- 期刊:
- 影响因子:1.6
- 作者:Pasha,Saba;Smith,Lachlan;Sankar,WudbhavN
- 通讯作者:Sankar,WudbhavN
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Lachlan James Smith其他文献
Lachlan James Smith的其他文献
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{{ truncateString('Lachlan James Smith', 18)}}的其他基金
ORS Spine Section Symposia: Enhancing Spine Research throughMentoring, Diversity and Collaboration
ORS 脊柱部分研讨会:通过指导、多样性和协作加强脊柱研究
- 批准号:
10606748 - 财政年份:2023
- 资助金额:
$ 34.42万 - 项目类别:
Mechanisms of Vertebral Bone Disease in Mucopolysaccharidosis VII
粘多糖贮积症椎骨疾病的机制七
- 批准号:
8702431 - 财政年份:2014
- 资助金额:
$ 34.42万 - 项目类别:
Mechanisms of Vertebral Bone Disease in Mucopolysaccharidosis VII
粘多糖贮积症椎骨疾病的机制七
- 批准号:
9020928 - 财政年份:2014
- 资助金额:
$ 34.42万 - 项目类别:
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