Hormonal Control of Calcium Metabolism

描述(申请人提供)：这个名为“钙代谢的荷尔蒙控制”的项目汇集了一群工作效率高的研究人员，他们多年来一直密切合作，得到项目的支持，并受到内分泌科环境的刺激。强大的研究工具采用了化学和分子生物学的方法，以及一些精心设计的转基因动物来评估骨骼和肾脏细胞生物学以及矿物质代谢。这项工作已经启动了令人兴奋的医学翻译应用程序。项目I“甲状旁腺激素配体对甲状旁腺激素受体1的作用机制和体内影响”(Gardella Pi)导致了甲状旁腺功能减退症的新疗法的开发(与Nigh Bridgs计划合作)，在肽设计方面令人兴奋的新方向，包括信号选择性化合物和新型长效甲状旁腺素分子，以及多肽仿制(与NlH的小分子筛选计划MLPCN合作)。项目II“PTH对成骨细胞系细胞的作用”(Kronenberg Pi)和项目III“PTH/PTHrP受体和RANKL在体内成骨细胞中的作用”(Divieti Pajevic Pi)是两个独立但密切相关的项目，它们利用研究人员开发的强大的新技术来探索骨骼中对PTH的细胞响应，以研究体内成骨细胞系细胞的增殖和分化，组蛋白脱乙酰酶在PTH骨合成代谢作用中的作用以及不同分化阶段成骨细胞中PTH受体缺失的结果。这项工作对于了解如何在骨折愈合和骨质疏松症患者中改善甲状旁腺素的治疗反应是基本的。项目四，“甲状旁腺素在肾脏磷酸盐排泄调节中对肾脏靶细胞的作用”(Jueppner PI)，研究了甲状旁腺素作用中信号选择性的关键特征，特别是在肾脏磷酸盐转运和慢性甲状旁腺素暴露时cAMP/PKA途径的脱敏以及随后通过IP3/PKC途径的补偿，强调了甲状旁腺素配体与IP3/PKC信号增强在改善慢性肾脏疾病(CKD)治疗方面的潜在作用。

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).