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
• 负责人: Wenhan Chang
• 金额: $ 227.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10668177
• 关键词: Ablation; Acids; Acute; Affect; Aging; Alleles; Amino Acids; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Attenuated; Binding; Bone Density; Calcium; Calcium Signaling; Calcium-Sensing Receptors; Cells; Clinical; Clinical Research; Complex; Coupling; Cyclic AMP; Data; Development; Dimerization; Disease; Down-Regulation; Elderly; Endocrine Glands; Endocrine System Diseases; Enzymes; Etiology; Event; Fluorescence Resonance Energy Transfer; GTP-Binding Proteins; Genes; Genetic Transcription; Glutamate Decarboxylase; Health; Homeostasis; Hormonal; Hormone secretion; Human; Hypercalcemia; Hyperparathyroidism; Image; Knockout Mice; Ligands; Link; MAPT gene; Mediating; Microtubules; Minerals; Modeling; Molecular; Mus; Muscle Weakness; Neurons; Outcome; PTH gene; Parathyroid Neoplasms; Parathyroid gland; Pathological fracture; Pathway interactions; Patients; Peptide Signal Sequences; Peptides; Phosphorylation; Physiological; Production; Property; Proteins; Rattus; Receptor Signaling; Reporter; Reporting; Role; Second Messenger Systems; Secondary to; Serum; Serum Calcium Level; Severity of illness; Signal Induction; Signal Transduction; Signaling Molecule; Testing; Therapeutic Intervention; Tissues; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Vulnerable Populations; Work; amyloid peptide; beta secretase; beta-arrestin; beta-site APP cleaving enzyme 1; body system; bone; bone loss; calcium metabolism; defined contribution; dihydroxy-vitamin D3; effective therapy; extracellular; fall risk; gamma secretase; gamma-Aminobutyric Acid; inhibitor; mouse model; neutralizing antibody; presenilin-1; prevent; receptor; receptor expression; response; secretase; tau Proteins; tau expression; tau-1; tau-protein kinase; trafficking; transcriptome; transcriptomics; treatment strategy

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.

抽象的 维生素D缺乏症是较早的宽度问题，可以使后遗症沉淀 对这个脆弱人群特别有害。甲状旁腺功能亢进（HPT）通常与低相关 维生素D状态以及该疾病的基本特征的钙稳态的破坏可能导致 古老的一系列有害结果，包括骨密度的丧失，肌肉无力和 跌倒和病理骨折的风险增加。作为负责骑马的主要内分泌器官 控制血清钙水平，甲状旁腺是维生素D作用的已知靶标 我们对维生素D缺乏症和减弱维生素D受体（VDR）的理解是主要差距 信号传导有助于HPT的病因和临床表现。机械中间体连接 HPT中的VDR到甲状旁腺骑马（PTH）过度分泌仍然未知，并且当前VDR-模型 甲状旁腺中钙传感接收器（CASR）的依赖表达不解释 在甲状旁腺组织中CASR抽象下调的HPT病例中的很大比例不是 观察到。最近，我们小组的几个关键发现提出了一种可测试的维生素D介导的新模型 甲状旁腺的作用。首先，我们表明GABA B1受体（GABAB1R）可以形成异二聚体 与CASR的复合物，通过反对CASR的耦合与其专有性的耦合来促进PTH的滋补过度分泌 下游G蛋白效应GQ/11和GI。其次，基于最近的一份报告，证明了可溶性 淀粉样蛋白前体蛋白（APP）的肽衍生物可以结合并激活神经元中的Gabab1r，我们发现 APP衍生的肽Aβ1-42可以增加CASR和CASR和甲状旁腺组织的最大PTH分泌 GABAB1R依赖性方式。 VDR表达和血清维生素D水平与 APP，Aβ1-42的相对丰度，Aβ1-42产生所需的γ-和β-分泌酶以及磷酸化的 微管相关蛋白tau（PTAU）的形式。在功能上，甲状旁腺中的应用程序消融 杂技在VDR KO小鼠中的HPT发展，而Tau磷酸化的抑制剂可以阻止能力 aβ1-42的促进PTH降压。这些数据表明，由VDR活动损失驱动的HPT可能 至少部分通过Aβ1-42和PTAU的不受管制的表达而产生。基于这些发现，我们 假设衰老诱导的Aβ1-42介导的信号传导的增加驱动滋补pth pth sypredsetripion，并且 维生素D缺乏通过缓解Aβ1-42产生的抑制和 tau/ptau表达。为了测试该模型，我们提出了三个完整的，机械特定的目的：（1） 描述Aβ1-42对CASR，GABAB1R和下游信号事件的分子作用 pth sypercretion; （2）确定阻塞Aβ1-42和TAU的生产或活性是否延迟HPT 在CASR不足的鼠模型中发展； （3）描述VDR之间的因果关系 甲状旁腺中的Aβ1-42/PTAU信号传导。通过定义CASR/GABAB1R/Aβ1-42的贡献 信号轴至PTH超过分泌，这项工作将提供更清晰的机械理解 β-淀粉样蛋白肽，维生素D状态和甲状旁腺功能之间的意外联系。