Role of Glutamine Metabolism During Osteoblast Differentiation and Bone Formation

谷氨酰胺代谢在成骨细胞分化和骨形成中的作用

基本信息

批准号：
10379301
负责人：
Courtney Michael Karner
金额：
$ 35.72万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379301
关键词：
Affect Alleles American Amino Acids Anabolism Biological Bone Development Bone Regeneration Bone Resorption Bone necrosis Catabolism Cells Chronic Citric Acid Cycle Data Disease Doxycycline Enzymes Femoral Fractures Future GCLC gene Glutamate-Cysteine Ligase Glutamates Glutaminase Glutamine Glutathione Health Care Costs Human Jaw Life Maintenance Marrow Mediating Mesenchymal Stem Cells Metabolic Metabolism Molecular Mus Natural regeneration Nucleotides Obesity Osteoblasts Osteogenesis Osteoporosis Osteoporotic Oxidative Stress Pathologic Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phenocopy Phosphotransferases Physiological Proteins Regulation Risk Role Signal Transduction Pathway Specific qualifier value Testing Therapeutic WNT Signaling Pathway Wild Type Mouse Work adipocyte differentiation base bone bone health bone mass cell fate specification conditionally essential amino acid defined contribution genetic approach in vivo insight mouse model new therapeutic target novel osteoblast differentiation prevent protein expression repaired skeletal stem cell differentiation stem cell fate specification stem cell population

项目摘要

Project Summary: Glutamine is a conditionally essential amino acid that has myriad uses in the cell. Aside from direct incorporation into protein, glutamine can be metabolized to generate nucleotides, other amino acids, ATP after anaplerosis into the TCA cycle, and glutathione to protect against oxidative stress. It is unknown how osteoblasts utilize glutamine and when it is required during differentiation. We recently identified glutaminase (GLS) as a critical regulator of Wnt dependent pathological bone formation. GLS deaminates glutamine to form glutamate, the first step in glutamine metabolism. Using a pharmacological approach, we demonstrated GLS activity was required for bone formation in the LRP5 human high bone mass disease mouse model. Importantly, GLS inhibition did not affect bone mass in otherwise wild type mice indicating GLS and glutamine metabolism may not be required for physiological bone formation in mice. In this proposal, we will 1) establish the necessity and sufficiency of glutaminase (GLS) to regulate osteoblast differentiation and bone formation, 2) determine if the molecular regulation of GLS activity by WNT, and 3) understand how glutamine is metabolized in mesenchymal stem cells. Our findings will have broad implications in bone development, maintenance of bone mass, skeletal repair and regeneration, as well as identify if stimulating glutamine metabolism is a viable osteoanabolic target to stimulate bone formation.

项目概要：谷氨酰胺是一种条件必需氨基酸，在细胞中具有多种用途。除了直接谷氨酰胺掺入蛋白质后可代谢生成核苷酸、其他氨基酸、ATP 回补进入 TCA 循环，谷胱甘肽可防止氧化应激。未知如何成骨细胞在分化过程中需要时利用谷氨酰胺。我们最近发现了谷氨酰胺酶 (GLS) 作为 Wnt 依赖性病理性骨形成的关键调节剂。 GLS 将谷氨酰胺脱氨基形成谷氨酸，这是谷氨酰胺代谢的第一步。使用药理学方法，我们证明了 LRP5 人类高骨量疾病小鼠模型中的骨形成需要 GLS 活性。重要的是，GLS 抑制不会影响其他野生型小鼠的骨量，表明 GLS 和谷氨酰胺小鼠的生理性骨形成可能不需要新陈代谢。在本提案中，我们将 1）建立谷氨酰胺酶（GLS）调节成骨细胞分化和骨形成的必要性和充分性，2）确定 WNT 是否对 GLS 活性进行分子调节，以及 3) 了解谷氨酰胺如何代谢在间充质干细胞中。我们的研究结果将对骨骼发育、维持骨量、骨骼修复和再生，以及确定刺激谷氨酰胺代谢是否可行刺激骨形成的骨合成代谢目标。