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们老龄化人口的主要公共卫生问题。治疗的新骨合成代谢策略迫切需要这种疾病。甲状旁腺马酮（PTH）是钙的中心调节剂稳态。通过其在骨骼中的快速作用，PTH迅速解放了钙的骨骼储存并维持正常血钙水平。另外，PTH还刺激骨形成，并在每天注射一次（teriparatide和鲍帕丁肽）进行骨质疏松治疗的形式。广泛使用 PTH疗法受到日常注射的需求的限制。此外，我们仍然不完全理解为什么间歇性PTH有效地构建骨骼，同时继续进行甲状旁腺功能亢进，导致骨骼质量损失一些抑制成骨细胞活性。在该研究计划中，我们将了解PTH如何刺激骨形成，然后使用该信息来发展下一代口服可用的骨合代代谢疗法。针对这些目标，我们最近将盐诱导激酶（SIK）的作用定义为关键细胞内骨细胞中甲状旁腺激素作用的介体。 PTH通过环状AMP和蛋白激酶信号传导 A阻断细胞中的SIK2和SIK3活性。彼此之间，遗传和药物实验策略阻止SIK2/SIK3活性有效地模仿PTH在骨骼中的作用。在AIM 1中，我们将开发，评估，并测试“下一代”口服可用的化合物，可阻止SIK2/SIK3动作并增强骨形成和临床前性腺功能减退相关的骨质疏松模型中的骨量。这样，我们将合并遗传和药物方法以确保这些化合物确实通过其预期靶标起作用（SIK2和SIK3）刺激骨形成。已经证明了新颖的小型治疗效率分子sik2/sik3抑制剂，接下来，我们将定义它们在AIM 2中的骨细胞中的作用机理。磷酸化蛋白质分析揭示了磷酸肌醇3-激酶和Akt信号的潜在控制。 PTH/SIK途径。该观察结果可以解释为什么连续的甲状旁腺功能亢进无法完全刺激成骨细胞形成骨骼。在这里，我们将研究PTH/SIK信号如何与Akt途径相交细胞水平的骨细胞，然后使用此信息测试降低AKT的模型活动有助于解释由于连续的甲状旁腺功能亢进而引起的骨质流失。两者一起，这些相关目标将阐明骨细胞中的新型信号转导模型，并定义A的作用机理新的，口服可用的骨质疏松症骨合成代谢疗法。