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老龄化人口中的一个主要公共卫生问题。新的骨合成代谢治疗策略。这种疾病迫切需要甲状旁腺激素（PTH），它是钙的主要调节剂。 PTH 通过其在骨骼中的快速作用，快速释放骨骼中储存的钙并维持体内平衡。正常的血钙水平此外，PTH 还刺激骨形成，并且这种特性被利用于每日一次注射（特立帕肽和阿巴洛帕肽）的形式广泛用于骨质疏松症治疗。 PTH 治疗因需要每日注射而受到限制，此外，我们仍然不完全了解原因。间歇性 PTH 可有效构建骨骼，而持续性甲状旁腺功能亢进会导致骨质流失，在这个研究项目中，我们将了解 PTH 如何刺激成骨细胞活性。骨形成，然后利用该信息开发下一代口服骨合成代谢药物为了实现这些目标，我们最近将盐诱导激酶（SIK）定义为关键的细胞内药物。甲状旁腺激素在骨细胞中通过环 AMP 和蛋白激酶发挥作用的介质。 A 阻断细胞中的 SIK2 和 SIK3 活性，因此，遗传和药理学实验策略阻断 SIK2/SIK3 活性，有效模拟骨骼中 PTH 的作用。在目标 1 中，我们将开发、评估、并测试阻断 SIK2/SIK3 作用并促进骨形成的“下一代”口服化合物和临床前性腺机能减退相关骨质疏松症模型中的骨量在此过程中，我们将合并。遗传和药理学方法确保这些化合物确实通过其靶点发挥作用（SIK2和SIK3）刺激骨形成具有新颖的小治疗功效。 SIK2/SIK3 分子抑制剂，接下来我们将在目标 2 中定义它们在骨细胞中的作用机制。磷酸蛋白质组分析揭示了磷酸肌醇 3-激酶和 AKT 信号传导的潜在控制这一观察结果可能解释了为什么持续性甲状旁腺功能亢进未能充分刺激。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上，然后使用此信息来测试减少 AKT 的模型活动有助于解释持续性甲状旁腺功能亢进引起的骨质流失。总而言之，这些都是相互关联的。目标将阐明骨细胞中的新型信号转导模型，并定义骨细胞的作用机制。新的口服骨质疏松症骨合成代谢疗法。