The Endocrine and Skeletal Actions of the PTG-derived Cyp27b1

PTG 衍生的 Cyp27b1 的内分泌和骨骼作用

• 批准号: 9261385
• 负责人: Amanda Herberger
• 金额: $ 5.92万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-04 至 2019-04-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9261385
• 关键词: Address; Adult; Advanced Development; Adverse effects; Animal Model; Animals; Biology; Blood; Bone Resorption; CYP27B1 gene; Calcitriol; Calcium; Cardiovascular system; Cells; Cellular biology; Childhood; Chronic Kidney Failure; Clinical; Development; Dihydroxycholecalciferols; Disease; Dose; Endocrine; Enzymes; Fellowship; Gene Expression; Genetic; Genetic Transcription; Gland; Goals; Granulomatous; Growth; Histology; Homeostasis; Hormonal; Human; Hypercalcemia; Hyperparathyroidism; Hypocalcemia result; Hypophosphatemia; Impairment; Intestines; Kidney; Knockout Mice; Knowledge; Lead; Link; Measurement; Metabolism; Minerals; Molecular Profiling; Mus; Operative Surgical Procedures; Organ Culture Techniques; Osteogenesis; Osteomalacia; PTH gene; Parathyroid gland; Pathologic; Patients; Phenotype; Physiological; Physiology; Production; Property; Proteins; RNA; Regimen; Regulation; Renal function; Research; Rickets; Role; Sarcoidosis; Scientist; Secondary Hyperparathyroidism; Seminal; Series; Serum; Serum Calcium Level; Source; System; Technical Expertise; Testing; Tissues; Training; VDR gene; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; X-Ray Computed Tomography; absorption; bone; experimental study; knockout gene; mouse model; paracrine; parathyroid hormone (1-34); protein expression; public health relevance; receptor; skeletal; skills; targeted treatment

 DESCRIPTION (provided by applicant): Dysregulation of vitamin D metabolism can lead to several diseases including hypercalcemia, secondary hyperparathyroidism, hypocalcemia, hypophosphatemia, rickets, osteomalacia and growth retardation. The bioactive form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D), is made by the enzyme Cyp27b1 (25- dihydroxyvitamin D 1-alpha hydroxylase). Renal Cyp27b1 has long been considered the primary source of circulating 1,25D. This 40-year principle was established mainly from the observation that decreased renal function is strongly associated with decreased serum 1,25D levels in anephric animal models and patients with chronic kidney disease. It is well known that parathyroid hormone (PTH) activates its renal receptors to increase Cyp27b1 expression, and subsequently, to elevate serum 1,25D levels. However, these paradigms fit basic observations that do not take into account the fact that many tissues express the 1-alpha hydroxylase and generate 1,25D. Our preliminary studies in mice with vitamin D receptor (VDR) or Cyp27b1 gene knockout targeted specifically to parathyroid cells suggest that the Cyp27b1 expressed in parathyroid gland (PTG) could be a major source of circulating 1,25D and exert endocrine actions on mineral and skeletal homeostasis. We further found that the incubation of freshly isolated mouse PTGs with PTH(1-34) profoundly increased Cyp27b1 protein and RNA in these PTGs, indicating direct regulation of this enzyme by PTH. The above studies together led us to hypothesize that the parathyroid Cyp27b1 is a prominent source of circulating 1,25D that is subject to direct regulation by PTH and other hormonal and mineral factors. To test this hypothesis we will (1) determine the hormonal, mineral, and skeletal actions of PT-derived Cyp27b1 in the mouse model, and (2) determine the mechanisms and systemic factors that regulate Cyp27b1 expression and function in the PTG. Successful completion of this fellowship project will lend support to new regulatory paradigms for vitamin D and mineral metabolism and will provide me with essential training in parathyroid physiology, cell biology, vitamin D metabolism and mouse genetics, and will expand my technical skills in my development as an independent research scientist.

 描述（申请人提供）：维生素D代谢失调可导致多种疾病，包括高钙血症、继发性甲状旁腺功能亢进、低钙血症、低磷血症、佝偻病、骨软化症和生长迟缓。维生素 D 的生物活性形式 1,25-二羟基维生素 D3 (1,25D) 由 Cyp27b1（25-二羟基维生素 D 1-α 羟化酶）产生。长期以来，肾脏 Cyp27b1 一直被认为是循环 1,25D 的主要来源。这一长达 40 年的原则主要是根据以下观察结果建立的：肾功能下降与肾病动物模型和慢性肾病患者血清 1,25D 水平下降密切相关。众所周知，甲状旁腺激素 (PTH) 激活其肾受体以增加 Cyp27b1 表达，随后提高血清 1,25D 水平。然而，这些范例符合基本观察结果，但没有考虑到许多组织表达 1-α 羟化酶并生成 1,25D 的事实。我们对维生素 D 受体 (VDR) 或专门针对甲状旁腺细胞的 Cyp27b1 基因敲除的小鼠进行的初步研究表明，甲状旁腺 (PTG) 中表达的 Cyp27b1 可能是循环 1,25D 的主要来源，并对矿物质和骨骼稳态发挥内分泌作用。我们进一步发现，将新鲜分离的小鼠 PTG 与 PTH(1-34) 一起孵育可显着增加这些 PTG 中的 Cyp27b1 蛋白和 RNA，表明 PTH 对该酶的直接调节。上述研究共同使我们推测甲状旁腺 Cyp27b1 是循环 1,25D 的重要来源，它受到 PTH 和其他激素和矿物质因子的直接调节。为了检验这一假设，我们将 (1) 确定 PT 衍生的 Cyp27b1 在小鼠模型中的激素、矿物质和骨骼作用，以及 (2) 确定调节 PTG 中 Cyp27b1 表达和功能的机制和系统因素。该奖学金项目的成功完成将为维生素 D 和矿物质代谢的新监管范式提供支持，并将为我提供甲状旁腺生理学、细胞生物学、维生素 D 代谢和小鼠遗传学方面的基本培训，并将扩展我作为独立研究科学家的发展的技术技能。