Regulation of parathyroid function by the amyloid precursor protein
淀粉样前体蛋白对甲状旁腺功能的调节
基本信息
- 批准号:10225816
- 负责人:
- 金额:$ 28.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAffectAgeAgingAmyloidAmyloid Beta A4 Precursor ProteinAmyloid beta-ProteinAmyloid beta-Protein PrecursorAttenuatedBehaviorBindingBinding ProteinsBiochemicalBiological AssayBiological ModelsCalciumCalcium SignalingCalcium-Sensing ReceptorsCell Culture TechniquesCellsChronicCleaved cellClinicalComplexCouplingDataDefectDiseaseDoseElderlyEndocrineEnzyme-Linked Immunosorbent AssayEvaluationFailureFeedbackFosteringFunctional disorderG-Protein-Coupled ReceptorsGABA-B ReceptorGTP-Binding ProteinsGenetic ModelsGlandHealthHeterogeneityHomeostasisHormonalHormone secretionHumanHypercalcemiaHyperparathyroidismHypoparathyroidismImpaired cognitionIn SituIn VitroIncidenceIndividualIntestinesKidneyKnock-outKnockout MiceLigandsLinkLoxP-flanked alleleMass Spectrum AnalysisMediatingMineralsMolecularMusMutationNeuronsNormal tissue morphologyOrganOrgan Culture TechniquesOutcomePTH geneParathyroid AdenomaParathyroid NeoplasmsParathyroid glandPathologicPathway interactionsPatientsPeptide HydrolasesPeptidesPhenotypePhysiologicalPopulationPost-Translational Protein ProcessingProductionPropertyProteinsPublishingRNAReceptor SignalingRegulationReportingRoleSeriesSerumSignal TransductionSubgroupSystemTestingTherapeutic InterventionTimeTissuesUp-RegulationVariantVulnerable PopulationsWorkadenomaage relatedalpha secretaseamyloid peptideamyloid precursor protein processingattenuationbasebehavioral responsebeta secretasebonebone masscalcium absorptioncalcium metabolismcomparativeexperimental studyfracture riskgamma secretasegamma-Aminobutyric Acidin vivoinnovationmicroCTmouse modelneoplasticnovelparacrinereceptorresponsesecretaseskeletaltranscriptomics
项目摘要
Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder that predominantly occurs in the elderly. PHPT affects 15 to 30 individuals per 100,000 in the U.S., an overall incidence that has been steadily rising as the nation’s mean population ages. The disease is biochemically defined by constitutively elevated secretion of parathyroid hormone (PTH) from neoplastic parathyroid tissue, leading to chronic hypercalcemia and a spectrum of clinical sequelae including bone mass attrition and increased fracture risk. While the central physiological deficit in PHPT – the failure to maintain calcium homeostasis – is well recognized, the underlying molecular mechanisms that drive this systemic dysfunction have not been fully characterized. A major limitation to studying calcium sensing in normal and neoplastic parathyroid tissue has been the lack of experimentally tractable model systems that can faithfully reproduce the dynamic calcium response behaviors of the intact organ. To address this, our group has developed a series of ex vivo intact tissue assays that allow interrogative assessment of parathyroid gland function in response to dynamic changes in ambient calcium concentration. Through comparative assessment of normal and neoplastic human parathyroid tissue, we found molecular and biochemical functional heterogeneity among parathyroid adenomas that correlated to phenotypic variations in clinical presentation. In parallel, using a series of murine genetic models our group has recently demonstrated that heterocomplex formation between the calcium sensing receptor (CaSR) and the metabotropic GABAB1 receptor (GABAB1R) can attenuate calcium responsiveness, uncoupling PTH secretion from ambient calcium sensing. The abundance of GABAB1R/CaSR complexes was found to be increased in parathyroid adenomas from patients with PHPT, suggesting that upregulation of GABAB1R/CaSR heterodimer formation could contribute to the attenuation of calcium sensing in neoplastic parathyroid tissue. Indeed, based on recently published work in neuronal systems reporting that various cleaved peptides of the amyloid precursor protein (APP) bind and activate GABAB1R, we have found that tonic secretion of PTH by murine parathyroid tissue is stimulated by co-incubation with b-amyloid (Ab), a peptide cleavage product of APP. We further showed robust expression of APP and all 3 key secretases involved in cleavage of APP-related peptides (sAPPa, sAPPb, and Ab) in human parathyroid adenomas and murine parathyroid glands, implicating a novel paracrine mechanism that may foster functional heterogeneity in parathyroid adenomas. We propose to delineate this mechanism by (1) quantitating the expression of the various APP-derived peptides and determining their impact on calcium signaling and PTH secretion in normal and PHPT adenoma human parathyroid tissue; and (2) investigating the effects of parathyroid-specific APP knockout on mineral, skeletal, and hormonal homeostasis in vivo. The discovery of this entirely novel signaling axis represents a provocative new conceptual pathway potentially linking age-dependent post-translational processing of APP to the increased incidence of PHPT in the elderly.
原发性甲状旁腺功能亢进(PHPT)是一种常见的内分泌肿瘤疾病,主要发生在最古老的情况下。 PHPT在美国影响每100,000人的15至30个人,这一总体事件随着国家平均人口年龄的增长而稳步上升。该疾病是通过肿瘤甲状旁腺组织的甲状旁腺马酮(PTH)的组成型升高来定义的,导致慢性高钙血症和临床后遗症,包括骨骼质量损耗和增加的分裂风险。虽然PHPT中的中央物理防御 - 无法维持钙稳态 - 众所周知,但驱动这种系统功能障碍的基本分子机制尚未得到充分表征。在正常和肿瘤甲状旁腺组织中研究钙传感的主要局限性是缺乏实验可拖动的模型系统,这些模型系统可以忠实地繁殖完整器官的动态钙反应行为。为了解决这个问题,我们的小组开发了一系列的离体完整组织评估,这些评估允许对甲状旁腺功能的疑问评估,以响应环境钙浓度的动态变化。通过对正常和肿瘤的人甲状旁腺组织的比较评估,我们发现甲状旁腺腺瘤中的分子和生化功能异质性与临床表现中的表型变异相关。同时,使用一系列鼠类遗传模型我们的组最近证明,钙感应受体(CASR)与代谢性GABAB1受体(GABAB1R)之间的异质复合物形成可以减弱钙的反应性,从周围的钙传感中解脱出PTH的分泌。发现在PHPT患者的甲状旁腺腺瘤中,GABAB1R/CASR复合物的抽象增加了,这表明GABAB1R/CASR异二聚体形成的上调可能有助于导致肿瘤甲状旁腺甲状旁腺组织中钙感应的衰减。 Indeed, based on recently published work in neuronal systems reporting that various cleaved peptides of the amyloid precursor protein (APP) bind and activate GABAB1R, we have found that tonic secretion of PTH by murine parathyroid tissue is stimulated by co-incubation with b-amyloid (Ab), a Peptide cleavage product of APP.我们进一步展示了APP的强烈表达以及在人类甲状旁腺腺瘤和鼠甲状腺甲状腺中与APP相关的Petides(Sappa,Sappb和AB)裂解所涉及的所有3个关键秘诀,暗示了一种新型的旁分泌机制,可能促进副腺瘤中副腺瘤中的功能异质性。我们建议通过(1)定量各种应用程序衍生的宠物的表达来描述这种机制,并确定它们对正常和PHPT腺瘤人类甲状旁腺组织中钙信号传导和PTH分泌的影响; (2)调查甲状旁腺特异性APP敲除对体内矿物,骨骼和辣椒稳态的影响。这个完全新颖的信号轴的发现代表了一种挑衅性的新概念途径,可能将APP的翻译后处理与较旧的PHPT的增加相关。
项目成果
期刊论文数量(0)
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Wenhan Chang其他文献
Wenhan Chang的其他文献
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{{ truncateString('Wenhan Chang', 18)}}的其他基金
Vitamin D and beta-amyloid signaling in hyperparathyroidism
甲状旁腺功能亢进症中的维生素 D 和 β-淀粉样蛋白信号传导
- 批准号:
10668177 - 财政年份:2023
- 资助金额:
$ 28.26万 - 项目类别:
ShEEP Request for NanoString GeoMx Digital Spatial Profiling System
ShEEP 请求 NanoString GeoMx 数字空间剖析系统
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10741001 - 财政年份:2023
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$ 28.26万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10365254 - 财政年份:2021
- 资助金额:
$ 28.26万 - 项目类别:
Regulation of parathyroid function by the amyloid precursor protein
淀粉样前体蛋白对甲状旁腺功能的调节
- 批准号:
10398252 - 财政年份:2021
- 资助金额:
$ 28.26万 - 项目类别:
BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism
BCCMA:针对和抵抗不利于骨骼的条件的基础研究(遏制骨折):长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用
- 批准号:
10531570 - 财政年份:2021
- 资助金额:
$ 28.26万 - 项目类别:
Regulation of Parathyroid Functions By G-Protein Coupled Receptors
G 蛋白偶联受体对甲状旁腺功能的调节
- 批准号:
10468008 - 财政年份:2019
- 资助金额:
$ 28.26万 - 项目类别:
Regulation of Parathyroid Functions By G-Protein Coupled Receptors
G 蛋白偶联受体对甲状旁腺功能的调节
- 批准号:
10693870 - 财政年份:2019
- 资助金额:
$ 28.26万 - 项目类别:
Regulation of Parathyroid Functions By G-Protein Coupled Receptors
G 蛋白偶联受体对甲状旁腺功能的调节
- 批准号:
10222663 - 财政年份:2019
- 资助金额:
$ 28.26万 - 项目类别:
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