Hormonal Control of Calcium Metabolism

描述（由申请人提供）：该计划项目“钙代谢的激素控制”汇集了一群高效的研究人员，他们密切合作，因为他们多年来一直受到该项目的支持，并受到内分泌单位环境的刺激。强大的研究工具包括化学和分子生物学方法，以及一些精心设计的转基因动物，以评估骨和肾细胞生物学以及矿物质代谢。令人兴奋的医学翻译应用已经开始从这项工作。项目I，“PTH配体对PTHR 1的作用机制和体内影响”（Gardella PI），已经导致甲状旁腺功能减退症的新疗法的开发（与NIGH BrIDGs项目合作），激动人心的肽设计新方向，包括信号选择性化合物和新型长效PTH分子，以及肽模拟物（与NIH的小分子筛选项目MLPCN合作）。项目II，“PTH对成骨细胞系细胞的作用”（Kronenberg PI）和项目III，“体内成骨细胞中PTH/PTHrP受体和RANKL的作用”（Divieti Pajevic PI）是独立但密切相关的项目，其采用研究者开发的强大新技术来研究体内成骨细胞谱系细胞的增殖和分化，组蛋白去乙酰化酶在细胞对PTH的骨合成代谢作用的反应中的作用，以及在不同分化阶段的成骨细胞中PTH受体缺失的结果。这项工作是了解如何改善骨折愈合和骨质疏松症患者对PTH的治疗反应的基础。项目IV，“PTH在调节肾磷酸盐排泄中对肾靶细胞的作用”（Jueppner PI），检查了PTH作用中信号选择性的关键特征，特别是对肾磷酸盐转运和cAMP/PKA途径与慢性PTH暴露的脱敏以及随后的IP 3/PKC途径的补偿，强调PTH配体与增强的IP 3/PKC信号传导在改善慢性肾病（CKD）治疗中的潜在作用。

DESCRIPTION (provided by applicant): This Program Project "Hormonal Control of Calcium Metabolism" brings together a group of highly productive investigators who work closely together, as they have for years, supported by the project and stimulated by the environment of the Endocrine Unit. Powerful research tools feature the approaches of chemical and molecular biology and a number of carefully designed genetically modified animals to evaluate bone and renal cell biology as well as mineral metabolism. Exciting medical translational applications have already been initiated from this work. Project I, "Mechanisms of action of PTH ligands on the PTHR1 and implications in vivo" (Gardella PI), has led to the development of a new therapy for hypoparathyroidism (in collaboration with NIGH BrIDGs program), exciting new directions in peptide design including signal selective compounds and newer types of long-acting PTH molecules, as well as peptidomimetics (in collaboration with NlH's small molecule screening program MLPCN). Project II, "PTH actions on cells of the osteoblast lineage" (Kronenberg PI), and Project III, "Role of PTH/PTHrP receptor and RANKL in osteoblastic cells in vivo" (Divieti Pajevic PI), are independent but closely related projects that explore the cellular responses in bone to PTH employing powerful new techniques developed by the investigators to study the proliferation and differentiation of cells of the osteoblast lineage in vivo, roles of histone deacetylases in the cellular responses to bone anabolic actions of PTH and results of deletion of the PTH receptor in osteoblastic cells at varying stages of differentiation. This effort is fundamental to understanding how to improve the therapeutic response to PTH in fracture healing and in patients with osteoporosis. Project IV, "PTH actions on renal target cells in the regulation of renal phosphate excretion" (Jueppner PI), examines key features of signal selectivity in PTH action, especially on renal phosphate transport and the desensitization of the cAMP/PKA pathway with chronic PTH exposure with the ensuing compensation by the IP3/PKC pathway, emphasizing the potential role of PTH ligands with enhanced IP3/PKC signaling in improving treatment in chronic renal disease (CKD).