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The role of salt inducible kinases in parathyroid hormone action in bone

盐诱导激酶在骨甲状旁腺激素作用中的作用

基本信息

批准号：
10734125
负责人：
Marc Nathan Wein
金额：
$ 44.25万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10734125
关键词：
Acute Anabolic Agents Bioenergetics Biological Blood Bone Formation Stimulation Bone Resorption Calcium Cells Chronic Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Development Disease Endocrine Female Forteo Genetic Goals Homeostasis Hormones Hyperparathyroidism Hypogonadism In Vitro Injections Insulin Insulin-Like Growth Factor I Knowledge Lead Mediator Medical Methods Modeling Mus Nature Oral Oral Administration Osteoblasts Osteogenesis Osteoporosis Outcome Output PIK3CG gene PTH gene Pathway interactions Pharmaceutical Preparations Phosphatidylinositols Phosphorylation Phosphotransferases Property Proteins Proto-Oncogene Proteins c-akt Public Health Research Role Signal Pathway Signal Transduction Skeleton Structure Testing Therapeutic Time Treatment Efficacy adenylate kinase aging population bone bone cell bone loss bone mass bone strength drug discovery hormonal signals hormone analog hormone therapy in vivo inhibitor insight kinase inhibitor male next generation novel novel strategies novel therapeutics pharmacologic phosphoproteomics pre-clinical programs response salt-inducible kinase skeletal small molecule translational potential

项目摘要

Project Abstract Osteoporosis is a major public health problem in our aging population. New bone anabolic strategies to treat this disease are desperately needed. Parathyroid hormone (PTH) is a central regulator of calcium homeostasis. Through its rapid actions in bone, PTH quickly liberates skeletal stores of calcium and maintains normal blood calcium levels. In addition, PTH also stimulates bone formation, and this property is exploited in the form of once daily injections (teriparatide and abaloparatide) for osteoporosis treatment. Widespread use of PTH therapy is limited by the need for daily injections. In addition, we still do not fully understand why intermittent PTH effectively builds bone while continuous hyperparathyroidism leads to loss of bone mass and some suppression of osteoblast activity. In this research program, we will understand how PTH stimulates bone formation and then use that information to develop next generation orally available bone anabolic therapies. Towards those goals, we recently defined a role for salt inducible kinases (SIKs) as key intracellular mediators of the actions of parathyroid hormone in bone cells. PTH signaling via cyclic AMP and protein kinase A blocks SIK2 and SIK3 activity in cells. Accordingly, genetic and pharmacologic experimental strategies that block SIK2/SIK3 activity effectively mimic the actions of PTH in bone. Here, in Aim 1, we will develop, evaluate, and test ‘next generation’ orally available compounds that block SIK2/SIK3 action and boost bone formation and bone mass in preclinical hypogonadism-associated osteoporosis models. In doing so, we will merge genetic and pharmacologic approaches to ensure that these compounds indeed act via their intended targets (SIK2 and SIK3) to stimulate bone formation. Having demonstrated therapeutic efficacy of novel small molecule SIK2/SIK3 inhibitors, next we will define their mechanism of action in bone cells in Aim 2. Unbiased phospho-proteomic profiling revealed potential control of phosphoinositide 3-kinase and AKT signaling by the PTH/SIK pathway. This observation may explain why continuous hyperparathyroidism fails to fully stimulate bone formation by osteoblasts. Here we will study how PTH/SIK signaling intersects with the AKT pathway in bone cells at the level of cellular energetics, and then use this information to test the model that reduced AKT activity helps explain bone loss due to continuous hyperparathyroidism. Taken together, these inter-related Aims will elucidate novel signal transduction models in bone cells and define the mechanism of action of a new, orally-available osteoporosis bone anabolic therapy.

项目摘要骨质疏松症是我国人口老龄化的一个主要公共卫生问题。新的骨合成代谢治疗策略这种疾病是迫切需要的。甲状旁腺激素（PTH）是钙的中枢调节因子体内平衡通过其在骨骼中的快速作用，PTH迅速释放骨骼中储存的钙，正常的血钙水平此外，PTH还刺激骨形成，并且这种性质在骨形成中被利用。每日一次注射（teriparlitazone和abaloparlitazone）治疗骨质疏松症。广泛使用 PTH治疗受每日注射需求的限制。此外，我们还不完全明白为什么间歇性甲状旁腺激素有效地建立骨，而持续性甲状旁腺激素过多导致骨量丢失，成骨细胞活性受到一定抑制。在这项研究计划中，我们将了解PTH如何刺激骨形成，然后使用该信息开发下一代口服骨合成代谢治疗为了实现这些目标，我们最近确定了盐诱导激酶（SIKs）作为细胞内关键酶的作用。骨细胞中甲状旁腺激素作用的介质。通过环AMP和蛋白激酶的PTH信号传导 A阻断细胞中的SIK 2和SIK 3活性。因此，遗传和药理学实验策略，阻断SIK 2/SIK 3活性有效地模拟了PTH在骨中的作用。在这里，在目标1中，我们将开发，评估，并测试“下一代”口服化合物，阻断SIK 2/SIK 3作用并促进骨形成临床前性腺功能减退相关骨质疏松模型中的骨质量。在此过程中，我们将合并遗传和药理学方法，以确保这些化合物确实通过其预期的目标发挥作用 (SIK2和SIK 3）以刺激骨形成。已经证明了新的小剂量的治疗效果，分子SIK 2/SIK 3抑制剂，接下来我们将在目的2中定义它们在骨细胞中的作用机制。无偏磷酸化蛋白质组学分析揭示了磷酸肌醇3-激酶和AKT信号的潜在控制， PTH/SIK通路。这一观察结果可以解释为什么持续性甲状旁腺功能亢进不能充分刺激成骨细胞的骨形成。在这里，我们将研究PTH/SIK信号如何与AKT通路交叉，骨细胞在细胞能量学水平，然后使用这些信息来测试模型，减少AKT 活动有助于解释持续性甲状旁腺功能亢进导致的骨质流失。这些相互关联的目的将阐明新的信号转导模型在骨细胞和定义的作用机制，新的口服骨质疏松症骨合成代谢疗法。