气候变化领域集成服务门户(CCPortal): Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin

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DOI	10.1073/PNAS.2014213117
	Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin
	Harder J.M.; Guymer C.; Wood J.P.M.; Daskalaki E.; Chidlow G.; Zhang C.; Balasubramanian R.; Cardozo B.H.; Foxworth N.E.; Deering K.E.; Ouellette T.B.; Montgomery C.; Wheelock C.E.; Casson R.J.; Williams P.A.; John S.W.M.
发表日期	2021
ISSN	00278424
起始页码	33619
结束页码	33627
卷号	117 期号:52
英文摘要	Intraocular pressure-sensitive retinal ganglion cell degeneration is a hallmark of glaucoma, the leading cause of irreversible blindness. Here, we used RNA-sequencing and metabolomics to examine early glaucoma in DBA/2J mice. We demonstrate gene expression changes that significantly impact pathways mediating the metabolism and transport of glucose and pyruvate. Subsequent metabolic studies characterized an intraocular pressure (IOP)-dependent decline in retinal pyruvate levels coupled to dysregulated glucose metabolism prior to detectable optic nerve degeneration. Remarkably, retinal glucose levels were elevated 50-fold, consistent with decreased glycolysis but possibly including glycogen mobilization and other metabolic changes. Oral supplementation of the glycolytic product pyruvate strongly protected from neurodegeneration in both rat and mouse models of glaucoma. Investigating further, we detected mTOR activation at the mechanistic nexus of neurodegeneration and metabolism. Rapamycin-induced inhibition of mTOR robustly prevented glaucomatous neurodegeneration, supporting a damaging role for IOP-induced mTOR activation in perturbing metabolism and promoting glaucoma. Together, these findings support the use of treatments that limit metabolic disturbances and provide bioenergetic support. Such treatments provide a readily translatable strategy that warrants investigation in clinical trials. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Glaucoma; Neuronal metabolism; Neuroprotection; Pyruvate; Retinal ganglion cell
语种	英语
scopus关键词	glucose; neuroprotective agent; pyruvic acid; rapamycin; target of rapamycin kinase; animal; C57BL mouse; DBA mouse; disease model; drug effect; glaucoma; intraocular pressure; metabolism; nerve degeneration; neuroprotection; pathology; pathophysiology; retina; Sprague Dawley rat; Animals; Disease Models, Animal; Glaucoma; Glucose; Intraocular Pressure; Mice, Inbred C57BL; Mice, Inbred DBA; Nerve Degeneration; Neuroprotection; Neuroprotective Agents; Pyruvic Acid; Rats, Sprague-Dawley; Retina; Sirolimus; TOR Serine-Threonine Kinases
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179663
作者单位	Jackson Laboratory, Bar Harbor, ME 04609, United States; Ophthalmic Research Laboratories, Discipline of Ophthalmology and Visual Sciences, University of Adelaide, Adelaide, SA 5000, Australia; Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 77, Sweden; Department of Ophthalmology, Columbia University Irving Medical Center, New York, NY 10027, United States; HHMI, Columbia University Irving Medical Center, New York, NY 10032, United States; Zuckerman Mind Brain Behavior Institute, Columbia University Medical Center, New York, NY 10027, United States; Division of Eye and Vision, Department of Clinical Neuroscience, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, 171 64, Sweden
推荐引用方式 GB/T 7714	Harder J.M.,Guymer C.,Wood J.P.M.,et al. Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin[J],2021,117(52).
APA	Harder J.M..,Guymer C..,Wood J.P.M..,Daskalaki E..,Chidlow G..,...&John S.W.M..(2021).Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Harder J.M.,et al."Disturbed glucose and pyruvate metabolism in glaucoma with neuroprotection by pyruvate or rapamycin".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).