Regulation of gastric and osteoclast acidification by Snx10
Snx10 对胃和破骨细胞酸化的调节
基本信息
- 批准号:9238655
- 负责人:
- 金额:$ 57.12万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-03 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAcidsAge-Related Bone LossAlbers-Schonberg diseaseBindingBlindnessBone DevelopmentBone ResorptionCalciumCalcium GluconateCandidate Disease GeneCellsCessation of lifeChildhoodClinicalComplexDefectDevelopmentDextransDiagnosisDietary CalciumDietary SupplementationDiseaseEarly EndosomeEmployee StrikesEndocytosisEndosomesEpitheliumExcisionExhibitsFacial paralysisFailureFamilyFamily memberFractureGTP BindingGastric Parietal CellsGastrointestinal tract structureGeneral PopulationGenesGeneticGoalsGolgi ApparatusHereditary DiseaseHomeostasisHumanHypocalcemia resultImpairmentIntestinesKnockout MiceLifeLinkLongevityMaintenanceMediatingMembraneMembrane ProteinsMental RetardationMolecularMusMutationOsteoclastsOsteoporosisOutcomeParietalPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacologyPhenotypePhospholipidsPlayProductionProtein FamilyProtein SortingsProteinsRecyclingRegulationResearchRicketsRoleSavingsSecretory VesiclesSeveritiesSkeletal systemSorting - Cell MovementSpecificityStomachTNFSF11 geneTNFSF5 geneTechnologyThinnessTransport VesiclesVesicleVesicle Transport PathwayWorkbasebonebone healthbone lossbone masscalcium absorptioncalcium supplementationcell typedeafnesseconomic impactgastrointestinal systemhealth economicsimprovedin vivoinfancyinfant deathintestinal homeostasismineralizationmortalitymouse modelnovelprematurepreventprotein complexprotein transportpublic health relevancesorting nexinstraffickinguptake
项目摘要
DESCRIPTION (provided by applicant): The health and economic impact of osteoporosis continues to make studies of bone resorption by osteoclasts a critically important research focus. Osteoclasts are exceptionally dependent on vesicular trafficking, which is essential for bone resorption. Consequently, disruption (genetic or pharmacological) of osteoclastic vesicle transport abolishes resorptive activity. Proteins of the Snx family are known to mediate endosomal sorting, endocytosis, recycling of membrane proteins, and trafficking between various endosomes and Golgi apparatus. We found Snx10, a family member expressed in osteoclasts and in the stomach, where it is required for acid production. We generated Snx10-deficient mice (Snx10ins/ins) via gene-trap technology and characterized the bone phenotype. Snx10ins/ins mice exhibit a complex phenotype that is a combination of osteopetrosis (due to impaired osteoclast resorption) and rickets (impaired mineralization due to impaired gastric acidification and poor calcium absorption) known as osteopetrorickets. The underlying mechanisms leading to osteopetrorickets are currently unknown. Based on these findings, we conclude that Snx10 is essential for bone homeostasis in vivo by regulating vesicular trafficking and therefore acid production in both osteoclasts and the stomach. In this proposal we will use cell-specific Snx10 ablation studies in bone and stomach to elucidate the molecular mechanisms by which Snx10 regulates both osteoclastic resorption and gastric acidification for bone homeostasis. This proposal has high significance as it will characterize a new candidate gene involved in the development of human bone diseases, including osteoporosis, and bone loss associated with calcium deficiency. These results will change the paradigm of therapy for osteopetrotic patients with mutations in Snx10 and other genes with similar patterns of expression and activities, whose gastric defect has been generally overlooked. Importantly, our findings will significantly advance our understanding of the molecular mechanisms controlling osteoclast function and the control of bone homeostasis by the gastrointestinal tract.
描述(由申请人提供):骨质疏松症的健康和经济影响继续使破骨细胞的骨吸收研究成为极其重要的研究重点,破骨细胞特别依赖于囊泡运输,这对于骨吸收检查、破坏(遗传或破坏)至关重要。破骨细胞囊泡运输的药理学)消除了再吸收活性 已知 Snx 家族的蛋白质介导内体分选、内吞作用和膜的再循环。我们发现 Snx10 是一种在破骨细胞和胃中表达的家族成员,它是产生酸所必需的,我们通过基因捕获技术生成了 Snx10 缺陷小鼠 (Snx10ins/ins)。并表征了 Snx10ins/ins 小鼠表现出的复杂表型,这是骨硬化症(由于破骨细胞吸收受损)和佝偻病(由于破骨细胞吸收受损)的组合。胃酸化受损和钙吸收不良),称为骨质疏松症。目前尚不清楚导致骨质疏松症的潜在机制。基于这些发现,我们得出结论,Snx10 通过调节破骨细胞和破骨细胞中的酸产生,对体内骨稳态至关重要。在本提案中,我们将在骨和胃中使用细胞特异性 Snx10 消融研究来阐明 Snx10 调节破骨细胞吸收的分子机制。该提议具有重要意义,因为它将描述与人类骨骼疾病(包括骨质疏松症和与钙缺乏相关的骨质流失)发展有关的新候选基因。这些结果将改变骨质疏松症的治疗模式。具有 Snx10 和具有相似表达和活动模式的其他基因突变的患者,其胃缺陷通常被忽视。重要的是,我们的发现将显着增进我们对控制破骨细胞功能和骨稳态控制的分子机制的理解。胃肠道。
项目成果
期刊论文数量(0)
专著数量(0)
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Ricardo Anibal Battaglino其他文献
Ricardo Anibal Battaglino的其他文献
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{{ truncateString('Ricardo Anibal Battaglino', 18)}}的其他基金
Regulation of Gastric and Osteoclat Acidification by Snx10
Snx10 对胃酸和骨酸化的调节
- 批准号:
10467087 - 财政年份:2021
- 资助金额:
$ 57.12万 - 项目类别:
Regulation of gastric and osteoclast acidification by Snx10
Snx10 对胃和破骨细胞酸化的调节
- 批准号:
9312578 - 财政年份:2016
- 资助金额:
$ 57.12万 - 项目类别:
Regulation of gastric and osteoclast acidification by Snx10
Snx10 对胃和破骨细胞酸化的调节
- 批准号:
8879662 - 财政年份:2015
- 资助金额:
$ 57.12万 - 项目类别:
Role of NHA-oc/NHA2 in Osteoclast Differentiation and Function
NHA-oc/NHA2 在破骨细胞分化和功能中的作用
- 批准号:
7990883 - 财政年份:2010
- 资助金额:
$ 57.12万 - 项目类别:
Role of NHA-oc/NHA2 in Osteoclast Differentiation and Function
NHA-oc/NHA2 在破骨细胞分化和功能中的作用
- 批准号:
8109218 - 财政年份:2010
- 资助金额:
$ 57.12万 - 项目类别:
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