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The role of proline metabolism during osteoblast differentiation and bone formation

脯氨酸代谢在成骨细胞分化和骨形成中的作用

基本信息

批准号：
10046912
负责人：
Courtney Michael Karner
金额：
$ 7.2万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2020-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046912
关键词：
ATP Synthesis Pathway Address Affect Alleles American Amino Acid Transporter Amino Acids Anabolism Back Bone Development Bone Matrix Bone Regeneration Bone Resorption Cell Proliferation Cell Survival Cells Collagen Complex Consumption Coupling Data Defect Disease Disease Progression Electron Transport Electrons Enzymes Glycolysis Health Care Costs Homeostasis Imino Acids In Vitro Individual Knowledge Maintenance Membrane Metabolic Metabolism Molecular Mus NADH Natural regeneration Neutral Amino Acid Transport Systems Osteoblasts Osteogenesis Osteopenia Osteoporosis Oxides Pathway interactions Patients Pentosephosphate Pathway Pharmaceutical Preparations Physiologic Ossification Physiological Process Production Proline Proline Dehydrogenase Protein Biosynthesis Proteins Regulation Role System WNT Signaling Pathway Work aminoacid biosynthesis base bone bone mass bone quality cancer cell carboxylate extracellular genetic approach in vitro activity in vivo metabolomics new therapeutic target osteoblast differentiation oxidation polypeptide prevent progenitor proline permease pyrroline pyrroline 5 carboxylate reductase repaired skeletal uptake

项目摘要

Project Summary: Proline is a multifunctional imino acid with myriad uses in the cell. Aside from direct incorporation into protein, proline can be metabolized via a process known as the proline cycle. Here, proline is oxidized by proline oxidase (PRODH) to form D1-pyrroline-5-carboxylate (P5C). PRODH is a FAD+ dependent enzyme that donates electrons to complex II of the mitorchondrial electron transport chain thus coupling proline oxidation to ATP synthesis. P5C is converted back into proline by the NADH dependent enzyme pyrroline-5-carboxylate reductase (PYCR) to provide reducing power for glycolysis and the pentose phosphate pathways. It is unknown how osteoblasts obtain proline, how proline uptake is regulated, or if and when the proline cycle is required during differentiation. Osteoblasts express a diverse array of membrane-tethered amino acid transporters to facilitate proline uptake. We have identified the system A neutral amino acid transporter SNAT2 (encoded by Slc38a2) as the most highly expressed putative proline transporter in osteoblasts. Our preliminary data indicates WNT stimulates proline uptake through SNAT2 that is necessary for osteoblast differentiation in vitro. Moreover, mice homozygous for a null allele of Slc38a2 (Slc38a2-/-) have defects in endochondral ossification. In this proposal, we will 1) establish the necessity of proline uptake through Slc38a2/SNAT2 to regulate osteoblast differentiation and bone formation in vivo, 2) determine how SNAT2 activity is regulated by WNT signaling and 3) elucidate the necessity of proline metabolism via the proline cycle in differentiating osteoblasts. Our findings will have broad implications in bone development, maintenance of bone mass, skeletal repair and regeneration.

项目总结: