Hormonal Control of Calcium Metabolism

《钙代谢的荷尔蒙调控》项目汇集了一批高度 多年来密切合作的富有成效的调查人员， 项目和其他资助的研究资助。化学、分子和细胞生物学工具 可用的精心设计的转基因动物被用来评估 骨和肾细胞生物学中的甲状旁腺激素。几个激动人心的医学翻译 这项工作已经提出了申请，显然还可能有更多的申请。 项目I(Gardella PI)PTHR1的配体结合和激活机制在前面的基础上进行了扩展 探索配体/受体激活的分子细节的工作，包括新获得的小分子 分子多肽学以及改变药物动力学和药物动力学的新的化学策略 因此，甲状旁腺素类似物的最终药效学。这一点具有重要的翻译意义 研究人员很快发现了一种长效甲状旁腺激素，用于治疗甲状旁腺功能减退症 即将进入第一阶段临床试验和多肽负性激动剂的开发 动物模型中控制遗传性多发性骨骼异常的前景 失调性詹森氏病。项目II(Kronenberg Pi)甲状旁腺素对成骨细胞的作用 Lineage建立在早期进展的基础上，发现了甲状旁腺激素的第一个特定细胞靶点 行动起来，丝绸之路。这一发现开辟了重要基础科学研究的新领域 PTH的作用模式，并具有重要的翻译意义，因为小的 已经发现的分子激酶抑制剂可能最终会导致一种口腔活性物质 对治疗骨质疏松症有用。与此同时，这些调查人员仍在继续调查 甲状旁腺激素对骨中甲状旁腺激素作用细胞靶点的影响 骨细胞。除了它的基本兴趣之外，这项工作还可以帮助理解如何 改善甲状旁腺激素的作用，因为已知它的作用在连续使用12个月或 更少，尽管还有剩余的骨骼缺陷。项目III(Jueppner Pi)肾脏调节 磷酸盐动态平衡及其对骨骼的影响与几个最近的新发现有关。第一 甲状旁腺素类似物的信号选择性在磷酸盐代谢和骨细胞成熟中的重要性 其次，骨骼转基因表达的高骨量的含义 Jansen‘s病(JMC转基因)也在研究一种新可用的NPT2A特异性抑制剂 可能被证明对高磷血症和慢性肾脏病的遗传性疾病有用。项目四(曼施塔特 盐诱导激酶在肾脏甲状旁腺激素作用中的作用建立在最近的 研究人员发现SIKK家族在甲状旁腺激素骨作用中的重要性 在初步工作中令人信服地证明，丝裂原激酶也是甲状旁腺素作用的关键。 肾脏。

Program Project "Hormonal Control of Calcium Metabolism" brings together a group of highly productive investigators who have worked closely together for a number of years supported by the project and other funded research grants. Tools of chemical molecular and cellular biology plus available carefully designed genetically modified animals are used to evaluate the role of parathyroid hormone in bone and renal cell biology. Several exciting medical translational applications have already come from this work and the potential for several more is evident. Project I (Gardella PI) Mechanisms of ligand binding and activation at the PTHR1 expands on earlier work that probes molecular details of ligand/receptor activation including newly available small molecule peptidomimetics as well as new chemical strategies to alter the pharmacokinetic and therefore ultimately pharmacodynamic of PTH analogs. Important translational implications from this work have been the discovery of a long-acting form of PTH for treatment of hypoparathyroidism soon to be entering phase 1 clinical trials and development of peptide negative agonists that show promise in animal models of controlling the multiple skeletal abnormalities seen in the hereditary disorder Jansen's disease. Project II (Kronenberg PI) PTH actions on cells of the osteoblast lineage builds on earlier progress with discovery of the first specific cellular target of PTH action the SIK kinases. This discovery opens a new field of important basic science investigation into the mode of action of PTH and has important translational implications in that the small molecule kinase inhibitors already discovered might ultimately lead to an orally active agent useful in the treatment of osteoporosis. Meantime these investigators continue to probe the effects of PTH on cellular targets of PTH action in bone from earliest precursors to mature osteoblasts and osteocytes. This work in addition to its fundamental interest could help with understanding how to improve PTH action since it is known that its effect wanes after continuous use for 12 months or less even though there are bone deficits remaining. Project III (Jueppner PI) renal regulation of phosphate homeostasis and its effects on bone deals with several recent novel findings. The first is importance of signal selectivity in PTH analogs in phosphate metabolism and bone cell maturation and secondly, the implications of high bone mass seen with skeletal transgenic expression of the Jansen's disease (JMC transgene) also studying a newly available specific inhibitor of NPT2A that may prove to be useful in hereditary disorders of hyperphosphatemia and CKD. Project IV (Mannstadt and Wein co-PI’s) The role of salt inducible kinases in renal PTH action builds on the recent discovery of the importance of the SIK kinase family in PTH bone action the investigators having demonstrated convincingly in preliminary work that SIK kinases are also critical to PTH actions on the kidney.