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（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）研究甲状旁腺特异性APP敲除对体内矿物，骨骼和骑马稳态的影响。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。