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：
Wenhan Chang
金额：
$ 28.26万
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：
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：
https://reporter.nih.gov/project-details/10225816
关键词：
Ablation Address Affect Age Aging Amyloid Amyloid Beta A4 Precursor Protein Amyloid beta-Protein Amyloid beta-Protein Precursor Attenuated Behavior Binding Binding Proteins Biochemical Biological Assay Biological Models Calcium Calcium Signaling Calcium-Sensing Receptors Cell Culture Techniques Cells Chronic Cleaved cell Clinical Complex Coupling Data Defect Disease Dose Elderly Endocrine Enzyme-Linked Immunosorbent Assay Evaluation Failure Feedback Fostering Functional disorder G-Protein-Coupled Receptors GABA-B Receptor GTP-Binding Proteins Genetic Models Gland Health Heterogeneity Homeostasis Hormonal Hormone secretion Human Hypercalcemia Hyperparathyroidism Hypoparathyroidism Impaired cognition In Situ In Vitro Incidence Individual Intestines Kidney Knock-out Knockout Mice Ligands Link LoxP-flanked allele Mass Spectrum Analysis Mediating Minerals Molecular Mus Mutation Neurons Normal tissue morphology Organ Organ Culture Techniques Outcome PTH gene Parathyroid Adenoma Parathyroid Neoplasms Parathyroid gland Pathologic Pathway interactions Patients Peptide Hydrolases Peptides Phenotype Physiological Population Post-Translational Protein Processing Production Property Proteins Publishing RNA Receptor Signaling Regulation Reporting Role Series Serum Signal Transduction Subgroup System Testing Therapeutic Intervention Time Tissues Up-Regulation Variant Vulnerable Populations Work adenoma age related alpha secretase amyloid peptide amyloid precursor protein processing attenuation base behavioral response beta secretase bone bone mass calcium absorption calcium metabolism comparative experimental study fracture risk gamma secretase gamma-Aminobutyric Acid in vivo innovation microCT mouse model neoplastic novel paracrine receptor response secretase skeletal transcriptomics

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症 (PHPT) 是一种常见的内分泌肿瘤疾病，在美国每 10 万人中就有 15 至 30 人患有 PHPT，总体发病率随着国家平均人口老龄化而稳步上升。甲状旁腺肿瘤组织分泌的甲状旁腺激素 (PTH) 持续升高，导致慢性高钙血症和包括骨量在内的一系列临床后遗症虽然 PHPT 的主要生理缺陷（无法维持钙稳态）已得到充分认识，但驱动这种系统功能障碍的潜在分子机制尚未得到充分表征，这是研究正常和钙传感的主要限制。肿瘤性甲状旁腺组织一直缺乏能够忠实再现完整器官的动态钙反应行为的实验易处理的模型系统。为了解决这个问题，我们的小组开发了一系列离体完整组织测定，可以对甲状旁腺功能进行质疑评估。在通过对正常和肿瘤性人类甲状旁腺组织的比较评估，我们发现甲状旁腺腺瘤的分子和生化功能异质性与临床表现的表型变异相关。研究小组最近证明，钙敏感受体（CaSR）和代谢型 GABAB1 受体（GABAB1R）之间形成的异质复合物可以减弱钙反应性，从而使 PTH 分泌与周围钙离子解偶联根据最近发表的研究，发现 PHPT 患者的甲状旁腺腺瘤中 GABAB1R/CaSR 复合物的丰度增加，这表明 GABAB1R/CaSR 异二聚体形成的上调可能有助于肿瘤性甲状旁腺组织中钙感应的减弱。在神经系统中工作，报告淀粉样前体蛋白 (APP) 的各种裂解肽结合并激活 GABAB1R，我们发现，小鼠甲状旁腺组织的 PTH 通过与 APP 的肽裂解产物 b-淀粉样蛋白 (Ab) 共孵育而受到刺激。我们进一步显示了 APP 以及参与 APP 相关肽（sAPPa、sAPPb）裂解的所有 3 种关键分泌酶的强劲表达。，和 Ab）在人甲状旁腺腺瘤和鼠甲状旁腺中，暗示一种新的旁分泌机制可能促进甲状旁腺的功能异质性我们建议通过（1）定量各种 APP 衍生肽的表达并确定它们对正常和 PHPT 腺瘤人甲状旁腺组织中钙信号和 PTH 分泌的影响；以及（2）研究甲状旁腺的影响来描述这一机制。 -体内矿物质、骨骼和激素稳态的特异性 APP 敲除这一全新信号轴的发现代表了一条可能与年龄依赖性相关的令人兴奋的新概念途径。 APP 翻译后加工导致老年人 PHPT 发病率增加。