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：
Wenhan Chang
金额：
$ 227.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
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

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.

抽象的维生素 D 缺乏是老年人中普遍存在的问题，可能会引发以下后遗症：对这一弱势群体尤其有害，甲状旁腺功能亢进症（HPT）通常与低水平有关。维生素 D 状态以及钙稳态破坏（这是该疾病的主要特征）可能会导致对老年人造成一系列有害后果，包括骨密度下降、肌肉无力和跌倒和病理性骨折的风险增加作为负责荷尔蒙的主要内分泌器官。控制血清钙水平，甲状旁腺是维生素 D 作用的已知目标，但我们对维生素 D 缺乏症和维生素 D 受体 (VDR) 减弱的认识存在重大差距信号传导有助于 HPT 的病因学和临床表现连接 HPT 的机制中间体。 HPT 中 VDR 与甲状旁腺激素 (PTH) 分泌过多的关系仍不清楚，目前的 VDR 模型甲状旁腺中钙敏感受体（CaSR）的依赖性表达并不能解释很大一部分 HPT 病例中甲状旁腺组织中的 CaSR 丰度并未下调最近，我们小组的几项重要发现提出了一种可测试的维生素 D 介导的新模型。首先，我们证明 GABA B1 受体 (GABAB1R) 可以形成异二聚体。与 CaSR 形成复合物，通过对抗 CaSR 与其专性的偶联来促进 PTH 的强直分泌过多下游 G 蛋白效应物 Gq/11 和 Gi 其次，基于最近的一份报告，证明可溶性。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GABAB1R APP 衍生肽 Aβ1-42 可以增加 CASR 中甲状旁腺组织的最大 PTH 分泌，并且 GABAB1R依赖方式的表达与血清维生素D水平呈负相关。 APP、Aβ1-42、Aβ1-42 生产所需的 γ- 和 β- 分泌酶的相对丰度以及磷酸化微管相关蛋白 Tau (pTau) 的形式在功能上消除甲状旁腺中的 APP。消除 VDR KO 小鼠 HPT 的发展，Tau 磷酸化抑制剂可以阻断这种能力 Aβ1-42 促进 PTH 过度分泌这些数据表明，VDR 活性丧失可能导致 HPT。至少部分是由于 Aβ1-42 和 pTau 的表达失控而产生的。衰老引起的 Aβ1-42 介导的信号传导增加会导致强效 PTH 分泌过多，并且维生素 D 缺乏通过缓解 Aβ1-42 产生和抑制而加剧 HPT 疾病的严重程度为了测试这个模型，我们提出了三个互补的、机制上的具体目标：(1) 描述 Aβ1-42 对 CaSR、GABAB1R 和促进下游信号事件的分子作用 (2) 确定阻断 Aβ1-42 和 Tau 的产生或活性是否会延迟 HPT CaSR 不足的小鼠模型的开发；(3) 描绘 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。 PTH 分泌过多的信号轴，这项工作将为人们提供更清晰的机制理解 β-淀粉样肽、维生素 D 状态和甲状旁腺功能之间存在意想不到的联系。