Mechanism of growth deficiency in dominant forms of osteogenesis imperfecta
Mechanism of growth deficiency in dominant forms of osteogenesis imperfecta
批准号:
10470299
负责人:
Satoru Otsuru
金额:
$33.65万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-09-01 至 2025-08-31
关键词:
3-DimensionalAddressAffectBone DiseasesBone GrowthBone MarrowCartilage DiseasesCellsCellular StressChestChondrocytesCollagenDataDefectDevelopmentDrug TargetingEndoplasmic ReticulumEnvironmentEpiphysial cartilageEventExposure toFunctional disorderGene Expression ProfilingGenesGeneticGenetic DiseasesGrowthHeightHistologicHistologyHypertrophyImmunoelectron MicroscopyImmunofluorescence ImmunologicImpairmentIn SituIn VitroLeadLengthMesenchymalMesenchymal DifferentiationModelingMusMusculoskeletalMutateMutationOsteoblastsOsteoclastsOsteogenesisOsteogenesis ImperfectaOutcomePathogenesisPathway interactionsPatientsPhenotypePhenylbutyratesPhysiologic OssificationPlayProcessProductionProliferatingProteinsReportingRespiratory FailureRoleSecondary toStainsStromal CellsSymptomsSystemTechniquesTestingTherapeuticTissuesTransplantationWild Type Mouseangiogenesisautosomal dominant mutationbiological adaptation to stressbisphosphonatebonebone fragilitycartilage cellcell typeclastogenesiseffective therapyendoplasmic reticulum stressexperimental studyimprovedinnovationlaser capture microdissectionlong bonemineralizationnovel therapeuticspreventresponseskeletalspine bone structurestandard carestemtransdifferentiation
中文摘要
项目总结
成骨不全(OI),被称为脆性骨骼疾病,是一种遗传性疾病,通常由
编码L胶原蛋白的两个基因之一的常染色体显性突变(COL1)。除了骨头之外
脆性、生长缺陷是OI的一个严重的肌肉骨骼问题。OI是没有治愈方法的。而当
双磷酸盐是强骨的标准治疗方法,目前还没有可靠有效的治疗方法
发育障碍。阻碍这种疗法发展的主要障碍之一是
COL1突变如何导致生长缺陷的机制尚未阐明。考虑到
改善成骨细胞功能的治疗对解决骨长度不足、细胞类型
成骨细胞以外的其他细胞可能参与了OI的生长迟缓。我们和其他人发现了
发生纵向骨骼生长的生长板,包括总高度增加,软骨细胞减少
更替和更少的增殖软骨细胞,表明突变的COL1以某种方式影响了软骨细胞
生长板。因此,了解软骨细胞缺陷的机制对发展至关重要。
OI生长缺陷的治疗。在这项提案中,我们将重点介绍使用G610C小鼠的优势OI
由于85-90%的OI是常染色体显性形式,因此存在Col1突变。我们的数据表明,OI
随着细胞的成熟,随着内质网的扩大,细胞开始表达col1,提示
与OI成骨细胞类似,OI HC暴露于更高的内质网应激。我们的初步研究表明
在颗粒培养中,G610C OI软骨细胞表达肥大表型的能力较低
内质网应激减压剂改善了这一缺陷,提示内质网应激不仅可能导致脑功能障碍。
成骨细胞也存在于OI的HCS中。事实上,已经表明,在HC中诱导内质网应激会导致HC
功能障碍并导致生长缺陷。总的来说,这些发现为我们的
内质网应激诱导的内质网功能障碍在生长缺陷中起关键作用的高度创新假说
占主导地位的OI。这一假设将通过支持以下具体目标的实验来解决:(1)
G610C OI小鼠Hcs内质网应激特征的研究(2)G610C OI小鼠Hcs功能障碍的研究
以及(3)从具有明显突变的显性OI患者中确定HCS中的内质网应激。完成度
这些目标将决定优势OI的生长缺陷是否是HC功能障碍的结果
由内质网压力引起。这一创新项目的成果有可能改变我们对OI的理解
通过不仅将OI定义为“骨骼疾病”,而且将其定义为“软骨疾病”,并提供了
专注于软骨细胞,而不是成骨细胞或破骨细胞,以制定生长治疗策略
其他投资减值。
英文摘要
PROJECT SUMMARY
Osteogenesis imperfecta (OI), known as a brittle bone disease, is a genetic disorder typically caused by
autosomal dominant mutations in one of the two genes that encode type l collagen (Col1). In addition to bone
fragility, growth deficiency is a critical musculoskeletal issue in OI. There is no cure for OI. While
bisphosphonates are the standard treatment to strengthen bones, there is no reliably effective treatment for
growth impairment. One of the major hurdles preventing the development of such treatments is that the
mechanism of how a mutation in Col1 causes growth deficiency has not been elucidated. Given that
treatments to improve osteoblast function were not effective for resolving bone length deficiency, cell types
other than osteoblasts might be involved in OI growth retardation. We and others found abnormalities in the
growth plate, where longitudinal bone growth occurs, including increased total height, decreased chondrocyte
turnover and fewer proliferating chondrocytes, suggesting that mutated Col1 somehow affects chondrocytes in
the growth plate. Thus, understanding the mechanism underlying chondrocyte defects is critical to develop
treatments for OI growth deficiency. In this proposal, we will focus on dominant OI using G610C mice
harboring Col1 mutation because 85-90% of OI are autosomal dominant forms. Our data demonstrated that OI
HCs began to express Col1 as they mature along with the enlarged endoplasmic reticulum (ER), suggesting
that OI HCs are exposed to higher ER stress similar to OI osteoblasts. Our preliminary studies demonstrated
that G610C OI chondrocytes had a lower ability to express hypertrophic phenotypes in pellet cultures and an
ER stress reducer ameliorated this defect, suggesting that ER stress may cause dysfunction not only in
osteoblasts but also in HCs in OI. Indeed, it has been shown that induction of ER stress in HCs causes HC
dysfunction and results in growth deficiency. Collectively, these findings provide rigorous premises for our
highly innovative hypothesis that HC dysfunction induced by ER stress plays a pivotal role in growth deficiency
of dominant OI. This hypothesis will be addressed by experiments supporting the following specific aims: (1) to
characterize ER stress occurring in HCs in G610C OI mice, (2) to determine HC dysfunction in G610C OI
mice, and (3) to determine ER stress in HCs from dominant OI patients with distinct mutations. The completion
of these aims will determine whether growth deficiency in dominant OI is a consequence of HC dysfunction
caused by ER stress. The outcome of this innovative project has potential to change our understanding of OI
by redefining OI not only as “bone disease” but also as “cartilage disease”, and by providing approaches
focused on chondrocytes, rather than osteoblasts or osteoclasts in developing therapeutic strategies for growth
impairment in OI.
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会议论文
Development of a novel therapy with Apolipoprotein E for osteogenesis imperfecta
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批准号:10038050
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项目类别:
-
资助金额:$20.39万
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财政年份:2020
-
负责人:Satoru Otsuru
-
依托单位:
Development of a novel therapy with Apolipoprotein E for osteogenesis imperfecta
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批准号:10262928
-
项目类别:
-
资助金额:$16.49万
-
财政年份:2020
-
负责人:Satoru Otsuru
-
依托单位:
Mechanism of growth deficiency in dominant forms of osteogenesis imperfecta
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批准号:10248521
-
项目类别:
-
资助金额:$32.97万
-
财政年份:2020
-
负责人:Satoru Otsuru
-
依托单位:
海外基金