Hormonal Control of Calcium Metabolism

“钙代谢的激素控制”项目汇集了一批高度专业的 多年来一直密切合作的富有成效的调查人员， 项目和其他资助的研究赠款。化学分子和细胞生物学工具 使用精心设计的转基因动物来评估 甲状旁腺激素在骨和肾细胞生物学中的作用。几个令人兴奋的医学翻译 这项工作已经有了应用，显然还有更多的应用潜力。 项目I（Gardella PI）PTHR 1的配体结合和激活机制在早期扩展 这项工作探测配体/受体激活的分子细节，包括新获得的小分子 分子肽模拟物以及新的化学策略来改变药代动力学， 因此最终是PTH类似物的药效学。重要的翻译影响，从这一点 工作已经发现了一种长效形式的PTH用于治疗甲状旁腺功能减退症 进入1期临床试验，并开发肽阴性激动剂， 在动物模型中控制遗传性骨骼畸形的希望 Jansen's disease詹森氏病项目II（Kronenberg PI）PTH对成骨细胞的作用 谱系建立在早期进展的基础上，发现了PTH的第一个特异性细胞靶点 作用于SIK激酶。这一发现开辟了重要的基础科学研究的新领域 进入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导致口服活性剂 可用于治疗骨质疏松症。与此同时，这些研究人员继续探索 从最早的前体细胞到成熟的成骨细胞， 骨细胞这项工作除了它的基本利益可以帮助理解如何 改善PTH作用，因为已知其作用在连续使用12个月后减弱，或 即使骨缺损仍然存在。项目III（Jueppner PI）肾脏调节 磷酸盐稳态及其对骨的影响涉及几个最近的新发现。第一 PTH类似物信号选择性在磷酸盐代谢和骨细胞成熟中的重要性 第二，骨骼转基因表达的高骨量的含义， Jansen病（JMC转基因）也在研究一种新的NPT 2A特异性抑制剂， 可能证明对高磷酸盐血症和CKD的遗传性疾病有用。项目四（曼施泰特 盐诱导激酶在肾PTH作用中的作用建立在最近的 由于发现了SIK激酶家族在PTH骨作用中的重要性， 在初步工作中令人信服地证明，SIK激酶对PTH的作用也至关重要， 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.