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
基本信息
- 批准号:10668177
- 负责人:
- 金额:$ 227.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-15 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcidsAcuteAffectAgingAllelesAmino AcidsAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnimalsAttenuatedBindingBone DensityCalciumCalcium SignalingCalcium-Sensing ReceptorsCellsClinicalClinical ResearchComplexCouplingCyclic AMPDataDevelopmentDimerizationDiseaseDown-RegulationElderlyEndocrine GlandsEndocrine System DiseasesEnzymesEtiologyEventFluorescence Resonance Energy TransferGTP-Binding ProteinsGenesGenetic TranscriptionGlutamate DecarboxylaseHealthHomeostasisHormonalHormone secretionHumanHypercalcemiaHyperparathyroidismImageKnockout MiceLigandsLinkMAPT geneMediatingMicrotubulesMineralsModelingMolecularMusMuscle WeaknessNeuronsOutcomePTH geneParathyroid NeoplasmsParathyroid glandPathological fracturePathway interactionsPatientsPeptide Signal SequencesPeptidesPhosphorylationPhysiologicalProductionPropertyProteinsRattusReceptor SignalingReporterReportingRoleSecond Messenger SystemsSecondary toSerumSerum Calcium LevelSeverity of illnessSignal InductionSignal TransductionSignaling MoleculeTestingTherapeutic InterventionTissuesVitamin DVitamin D DeficiencyVitamin D3 ReceptorVulnerable PopulationsWorkamyloid peptidebeta secretasebeta-arrestinbeta-site APP cleaving enzyme 1body systembonebone losscalcium metabolismdefined contributiondihydroxy-vitamin D3effective therapyextracellularfall riskgamma secretasegamma-Aminobutyric Acidinhibitormouse modelneutralizing antibodypresenilin-1preventreceptorreceptor expressionresponsesecretasetau Proteinstau expressiontau-1tau-protein kinasetraffickingtranscriptometranscriptomicstreatment strategy
项目摘要
ABSTRACT
Vitamin D deficiency is a widespread problem among the elderly and can precipitate sequelae that are
particularly harmful to this vulnerable population. Hyperparathyroidism (HPT) is commonly associated with low
vitamin D status, and the disruption in calcium homeostasis that is the cardinal feature of this disease can lead
to a range of deleterious outcomes among the elderly, including loss of bone density, muscle weakness, and
increased risk of falls and pathological fracture. As the primary endocrine organs responsible for hormonal
control of serum calcium levels, the parathyroid glands are a known target for the actions of vitamin D, yet there
are major gaps in our understanding of how vitamin D deficiency and attenuated vitamin D receptor (VDR)
signaling contribute to the etiology and clinical presentation of HPT. The mechanistic intermediates linking the
VDR to parathyroid hormone (PTH) hypersecretion in HPT remain unknown, and the current model of VDR-
dependent expression of the calcium sensing receptor (CaSR) in the parathyroid does not account for the
significant proportion of HPT cases where downregulation of CaSR abundance in parathyroid tissue is not
observed. Recently, several key findings from our group suggest a testable new model for vitamin D-mediated
actions in the parathyroid gland. First, we showed that the GABA B1 receptor (GABAB1R) can form heterodimeric
complexes with CaSR, promoting tonic hypersecretion of PTH by opposing the coupling of CaSR with its obligate
downstream G-protein effectors Gq/11 and Gi. Second, building upon a recent report demonstrating that soluble
peptide derivatives of the amyloid precursor protein (APP) can bind and activate GABAB1R in neurons, we found
that the APP-derived peptide Aβ1-42 can increase maximal PTH secretion by parathyroid tissue in a CASR- and
GABAB1R-dependent manner. VDR expression and serum vitamin D levels are inversely correlated with the
relative abundance of APP, Aβ1-42, the γ- and β-secretases required for Aβ1-42 production, and the phosphorylated
form of the microtubule associated protein Tau (pTau). Functionally, ablation of APP in the parathyroid
abrogates the development of HPT in VDR KO mice, and inhibitors of Tau phosphorylation can block the ability
of Aβ1-42 to promote PTH hypersecretion. These data suggest that HPT driven by loss of VDR activity could
arise at least in part through unregulated expression of Aβ1-42 and pTau. Based on these findings, we
hypothesize that aging-induced increases in Aβ1-42-mediated signaling drive tonic PTH hypersecretion and that
vitamin D deficiency exacerbates HPT disease severity by relieving suppression of Aβ1-42 production and
Tau/pTau expression. To test this model, we propose three complementary, mechanistic specific aims: (1) to
delineate the molecular actions of Aβ1-42 on CaSR, GABAB1R, and downstream signaling events that promote
PTH hypersecretion; (2) to determine whether blocking the production or activity of Aβ1-42 and Tau delays HPT
development in a murine model of CaSR insufficiency; and (3) to delineate the causal relationship between VDR
and Aβ1-42/pTau signaling in the parathyroid. By defining the contributions of the CaSR/GABAB1R/Aβ1-42
signaling axis to PTH hypersecretion, this work will provide a clearer mechanistic understanding of the
unexpected connection between β-amyloid peptides, vitamin D status, and parathyroid gland function.
摘要
维生素D缺乏症是老年人中普遍存在的问题,
尤其是对这些弱势群体。甲状旁腺功能亢进(HPT)通常与低
维生素D状态,以及钙稳态的破坏,这是这种疾病的主要特征,
老年人中的一系列有害结果,包括骨密度损失,肌肉无力,
增加福尔斯和病理性骨折的风险。作为主要的内分泌器官,
控制血清钙水平,甲状旁腺是维生素D作用的已知靶点,然而,
是我们理解维生素D缺乏和减弱的维生素D受体(VDR)
信号传导有助于HPT的病因学和临床表现。机械中间体连接
HPT中VDR对甲状旁腺激素(PTH)分泌过多的影响尚不清楚,目前的VDR-
甲状旁腺中钙敏感受体(CaSR)的依赖性表达不能解释
甲状旁腺组织中CaSR丰度下调的HPT病例中,
观察最近,我们小组的几个关键发现提出了一个可测试的维生素D介导的新模型。
作用于甲状旁腺。首先,我们发现GABA B1受体(GABAB 1 R)可以形成异二聚体,
与CaSR复合,通过对抗CaSR与其专性配体的偶联,促进PTH的紧张性高分泌
下游G蛋白效应物Gq/11和Gi。第二,根据最近的一份报告,
我们发现,淀粉样前体蛋白(APP)的肽衍生物可以结合并激活神经元中的GABAB 1 R
APP衍生肽Aβ1-42可以增加CASR中甲状旁腺组织的最大PTH分泌,
GABAB 1 R依赖的方式。VDR表达和血清维生素D水平与糖尿病患者的年龄呈负相关。
APP、Aβ1-42、Aβ1-42产生所需的γ-和β-分泌酶以及磷酸化
微管相关蛋白Tau(pTau)。功能上,甲状旁腺APP消融
消除了VDR KO小鼠中HPT的发展,Tau磷酸化的抑制剂可以阻断HPT的能力。
Aβ1-42促进PTH高分泌。这些数据表明,由VDR活性丧失驱动的HPT可能
至少部分通过Aβ1-42和pTau的不受调节的表达而产生。基于这些发现,我们
假设衰老诱导的Aβ1-42介导的信号传导增加驱动紧张性PTH高分泌,
维生素D缺乏通过缓解Aβ1-42产生的抑制而加重HPT疾病的严重程度,
Tau/pTau表达。为了检验这个模型,我们提出了三个互补的、机械的具体目标:(1)
描述Aβ1-42对CaSR、GABAB 1 R和下游信号传导事件的分子作用,
PTH高分泌;(2)确定阻断Aβ1-42和Tau的产生或活性是否延迟HPT
在CaSR不足的小鼠模型中的发展;和(3)描述VDR与
和甲状旁腺中的Aβ1-42/pTau信号传导。通过定义CaSR/GABAB 1 R/Aβ1-42的贡献,
信号轴的PTH高分泌,这项工作将提供一个更清晰的机制的理解,
β-淀粉样肽、维生素D状态和甲状旁腺功能之间的意外联系。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Wenhan Chang其他文献
Wenhan Chang的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Wenhan Chang', 18)}}的其他基金
ShEEP Request for NanoString GeoMx Digital Spatial Profiling System
ShEEP 请求 NanoString GeoMx 数字空间剖析系统
- 批准号:
10741001 - 财政年份:2023
- 资助金额:
$ 227.06万 - 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:
$ 227.06万 - 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:
$ 227.06万 - 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:
10225816 - 财政年份:2021
- 资助金额:
$ 227.06万 - 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:
$ 227.06万 - 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:
$ 227.06万 - 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:
$ 227.06万 - 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:
$ 227.06万 - 项目类别:
相似国自然基金
具有抗癌活性的天然产物金霉酸(Aureolic acids)全合成与选择性构建2-脱氧糖苷键
- 批准号:22007039
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
海洋放线菌来源聚酮类化合物Pteridic acids生物合成机制研究
- 批准号:
- 批准年份:2019
- 资助金额:10.0 万元
- 项目类别:省市级项目
手性Lewis Acids催化的分子内串联1,5-氢迁移/环合反应及其在构建结构多样性手性含氮杂环化合物中的应用
- 批准号:21372217
- 批准年份:2013
- 资助金额:80.0 万元
- 项目类别:面上项目
对空气稳定的新型的有机金属Lewis Acids催化剂制备、表征与应用研究
- 批准号:21172061
- 批准年份:2011
- 资助金额:30.0 万元
- 项目类别:面上项目
钛及含钛Lewis acids促臭氧/过氧化氢体系氧化性能的广普性、高效性及其机制
- 批准号:21176225
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
基于Zip Nucleic Acids引物对高度降解和低拷贝DNA检材的STR分型研究
- 批准号:81072511
- 批准年份:2010
- 资助金额:31.0 万元
- 项目类别:面上项目
海洋天然产物Makaluvic acids 的全合成及其对南海鱼虱存活的影响
- 批准号:30660215
- 批准年份:2006
- 资助金额:21.0 万元
- 项目类别:地区科学基金项目
相似海外基金
Gene expression regulation in recurrent paediatric acute myeloid leukaemia by characterization of non-coding ribonucleic acids
通过非编码核糖核酸的表征研究复发性小儿急性髓性白血病的基因表达调控
- 批准号:
449784 - 财政年份:2020
- 资助金额:
$ 227.06万 - 项目类别:
Studentship Programs
Study of metabolism of sulfur-containing amino acids as anti-oxidant against the acute exacerbation of interstitial pneumonia
含硫氨基酸抗氧化代谢对间质性肺炎急性加重的研究
- 批准号:
16K19984 - 财政年份:2016
- 资助金额:
$ 227.06万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Omega 3 Fatty Acids Acute Neuroprotection via Mitochondria
Omega 3 脂肪酸通过线粒体提供急性神经保护作用
- 批准号:
9450547 - 财政年份:2015
- 资助金额:
$ 227.06万 - 项目类别:
Omega 3 fatty acids, acute neuroprotection via mitochondria
Omega 3 脂肪酸,通过线粒体提供急性神经保护
- 批准号:
10447712 - 财政年份:2015
- 资助金额:
$ 227.06万 - 项目类别:
Omega 3 fatty acids, acute neuroprotection via mitochondria
Omega 3 脂肪酸,通过线粒体提供急性神经保护
- 批准号:
10297604 - 财政年份:2015
- 资助金额:
$ 227.06万 - 项目类别:
Omega 3 Fatty Acids, Acute Neuroprotection Via Mitochondria
Omega 3 脂肪酸,通过线粒体提供急性神经保护
- 批准号:
10655664 - 财政年份:2015
- 资助金额:
$ 227.06万 - 项目类别:
Omega 3 Fatty Acids Acute Neuroprotection via Mitochondria
Omega 3 脂肪酸通过线粒体提供急性神经保护作用
- 批准号:
8996605 - 财政年份:2015
- 资助金额:
$ 227.06万 - 项目类别:
ACUTE EFFECTS OF OLANZAPINE ON PLASMA LEPTIN, GLUCOSE TOLERANCE FREE FATTY ACIDS
奥氮平对血浆瘦素、无葡萄糖耐量脂肪酸的急性影响
- 批准号:
7951282 - 财政年份:2009
- 资助金额:
$ 227.06万 - 项目类别:
SENSITIVITY TO ACUTE INSULIN MEDIATED SUPPRESSION OF PLASMA FREE FATTY ACIDS
对胰岛素介导的血浆游离脂肪酸急性抑制的敏感性
- 批准号:
7180051 - 财政年份:2005
- 资助金额:
$ 227.06万 - 项目类别:
SENSITIVITY TO ACUTE INSULIN MEDIATED SUPPRESSION OF PLASMA FREE FATTY ACIDS
对胰岛素介导的血浆游离脂肪酸急性抑制的敏感性
- 批准号:
6977013 - 财政年份:2003
- 资助金额:
$ 227.06万 - 项目类别: