• 四川大學華西第二醫(yī)院兒科 婦兒疾病與出生缺陷教育部重點實驗室（成都，610041）;

目的 綜述哺乳動物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）參與神經(jīng)系統(tǒng)損傷修復
的可能機制。 方法 廣泛查閱mTOR 與神經(jīng)系統(tǒng)損傷后神經(jīng)修復的相關文獻并進行綜合分析。 結(jié)果 mTOR 可整
合細胞外應激信號，進而調(diào)節(jié)多種細胞生物過程，參與神經(jīng)系統(tǒng)損傷修復。 結(jié)論 不同途徑調(diào)節(jié)mTOR 信號通路活性，
進而減輕神經(jīng)系統(tǒng)損傷尤其是應激性腦損傷。mTOR 可作為促進應激性腦損傷修復的新靶點。

引用本文： 陳洪菊,唐彬秩,屈藝,母得志. 哺乳動物雷帕霉素靶蛋白參與神經(jīng)系統(tǒng)損傷修復的研究進展及其延伸意義. 中國修復重建外科雜志, 2012, 26(5): 625-630. doi: 復制

1. Xiong T, Qu Y, Mu D, et al. Erythropoietin for neonatal brain injury: opportunity and challenge. Int J Dev Neurosci, 2011, 29(6): 583-591.
2. Pastor MD, Garcia-Yebenes I, Fradejas N, et al. mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J Biol Chem, 2009, 284(33): 22067-22078.
3. Yang Q, Guan KL. Expanding mTOR signaling. Cell Res, 2007, 17(8): 666-681.
4. Bilali F, Kumar P, Feerick J, et al. Hypoxia-induced hypomyelination in the developing brain is mammalian target of rapamycin-4E-binding protein-1 signaling dependent. Neuroreport, 2008, 19(6): 635-639.
5. Chen S, Atkins CM, Liu CL, et al. Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. J Cereb Blood Flow Metab, 2007, 27(5): 939-949.
6. Clarkson AN, Sutherland BA, Appleton I. The biology and pathology of hypoxia-ischemia: an update. Arch Immunol Ther Exp (Warsz), 2005, 53(3): 213-225.
7. Fahling M. Cellular oxygen sensing, signalling and how to survive translational arrest in hypoxia. Acta Physiol (Oxf), 2009, 195(2): 205-230.
8. Koh PO, Cho JH, Won CK, et al. Estradiol attenuates the focal cerebral ischemic injury through mTOR/p70S6 kinase signaling pathway. Neurosci Lett, 2008, 436(1): 62-66.
9. Chu CT. Eaten alive: autophagy and neuronal cell death after hypoxia-ischemia. Am J Pathol, 2008, 172(2): 284-287.
10. Hagberg H, Mallard C, Rousset CI, et al. Apoptotic mechanisms in the immature brain: involvement of mitochondria. J Child Neurol, 2009, 24(9): 1141-1146.
11. Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol, 2011, 69(5): 743-758.
12. Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis, 2008, 32(3): 329-339.
13. Blomgren K, Leist M, Groc L. Pathological apoptosis in the developing brain. Apoptosis, 2007, 12(5): 993-1010.
14. Deguil J, Perault-Pochat MC, Chavant F, et al. Activation of the protein p70S6K via ERK phosphorylation by cholinergic muscarinic receptors stimulation in human neuroblastoma cells and in mice brain. Toxicol Lett, 2008, 182(1-3): 91-96.
15. 陳洪菊, 屈藝, 母得志. mTOR信號通路的生物學功能. 生命的化學, 2010, 30(4): 555-561.
16. Li L, Qu Y, Li J, et al. Relationship between HIF-1α expression and neuronal apoptosis in neonatal rats with hypoxia-ischemia brain injury. Brain Res, 2007, 1180: 133-139.
17. Hanna SC, Heathcote SA, Kim WY. mTOR pathway in renal cell carcinoma. Expert Rev Anticancer Ther, 2008, 8(2): 283-292.
18. Lu DY, Liou HC, Tang CH, et al. Hypoxia-induced iNOS expression in microglia is regulated by the PI3-kinase/Akt/mTOR signaling pathway and activation of hypoxia inducible factor-1α. Biochem Pharmacol, 2006, 72(8): 992-1000.
19. Tang XD, Zhou X, Zhou KY. Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1alpha protein accumulation and vascular endothelial growth factor expression in human breast cancer cells. Acta Pharmacol Sin, 2009, 30(5): 605-616.
20. Jin X, Jin HR, Lee D, et al. A quassinoid 6alpha-tigloyloxychaparrinone inhibits hypoxia-inducible factor-1 pathway by inhibition of eukaryotic translation initiation factor 4E phosphorylation. Eur J Pharmacol, 2008, 592(1-3): 41-47.
21. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res, 2006, 66(11): 5549-5554.
22. García-Maceira P, Mateo J. Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy. Oncogene, 2009, 28(3): 313-324.
23. Li W, Petrimpol M, Molle KD, et al. Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2. Circ Res, 2007, 100(1): 79-87.
24. Land SC, Tee AR. Hypoxia-inducible factor 1 alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem, 2007, 282(28): 20534-20543.
25. Wang W, Jia WD, Xu GL, et al. Antitumoral activity of rapamycin mediated through inhibition of HIF-1alpha and VEGF in hepatocellular carcinoma. Dig Dis Sci, 2009, 54(10): 2128-2136.
26. Wang Y, Zhao Q, Ma S, et al. Sirolimus inhibits human pancreatic carcinoma cell proliferation by a mechanism linked to the targeting of mTOR/HIF-1 alpha/VEGF signaling. IUBMB Life, 2007, 59(11): 717-721.
27. Humar R, Kiefer FN, Berns H, et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) -dependent signaling. FASEB J, 2002, 16(8): 771-780.
28. Li L, Xiong Y, Qu Y, et al. The requirement of extracellular signal-related protein kinase pathway in the activation of hypoxia inducible factor 1 alpha in the developing rat brain after hypoxia-ischemia. Acta Neuropathol, 2008, 115(3): 297-303.
29. Li L, Qu Y, Mao M, et al. The involvement of phosphoinositid 3-kinase/Akt pathway in the activation of hypoxia-inducible factor-1 alpha in the developing rat brain after hypoxia-ischemia. Brain Res, 2008, 1197: 152-158.
30. Jaworski J, Sheng M. The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol, 2006, 34(3): 205-219.
31. Park KK, Liu K, Hu Y, et al. PTEN/mTOR and axon regeneration. Exp Neurol, 2010, 223(1): 45-50.
32. Grider MH, Park D, Spencer DM, et al. Lipid raft-targeted Akt promotes axonal branching and growth cone expansion via mTOR and Rac1, respectively. J Neurosci Res, 2009, 87(14): 3033-3042.
33. Liu K, Lu Y, Lee JK, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci, 2010, 13(9): 1075-1081.
34. Fraser MM, Bayazitov IT, Zakharenko SS, et al. Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience, 2008, 151(2): 476-488.
35. Johnston MV, Ishida A, Ishida WN, et al. Plasticity and injury in the developing brain. Brain Dev, 2009, 31(1): 1-10.
36. Corsini NS, Sancho-Martinez I, Laudenklos S, et al. The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair. Cell Stem Cell, 2009, 5(2): 178-190.
37. Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell, 2009, 20(7): 1992-2003.
38. Srinivas V, Bohensky J, Shapiro IM. Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells Tissues Organs, 2009, 189(1-4): 88-92.
39. Dello Russo C, Lisi L, Tringali G, et al. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol, 2009, 78(9): 1242-1251.
40. Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain injury. Autophagy, 2009, 5(2): 221-223.
41. Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem, 2010, 285(19): 14071-14077.
42. Shang J, Deguchi K, Yamashita T, et al. Antiapoptotic and antiautophagic effects of glial cell line-derived neurotrophic factor and hepatocyte growth factor after transient middle cerebral artery occlusion in rats. J Neurosci Res, 2010, 88(10): 2197-2206.
43. Kimura R, Okouchi M, Fujioka H, et al. Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K/Akt/mTOR/GCLc/redox signaling pathway. Neuroscience, 2009, 162(4): 1212-1219.
44. Mukherjee P, Mulrooney TJ, Marsh J, et al. Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol Cancer, 2008, 7: 37.
45. Koh PO. Melatonin prevents ischemic brain injury through activation of the mTOR/p70S6 kinase signaling pathway. Neurosci Lett, 2008, 444(1): 74-78.
46. Kotulska K, Larysz-Brysz M, Grajkowska W, et al. Cardiac rhabdomyomas in tuberous sclerosis complex show apoptosis regulation and mTOR pathway abnormalities. Pediatr Dev Pathol, 2009, 12(2): 89-95.
47. Opel D, Westhoff MA, Bender A, et al. Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res, 2008, 68(15): 6271-6280.
48. Annovazzi L, Mellai M, Caldera V, et al. mTOR, S6 and AKT expression in relation to proliferation and apoptosis/autophagy in glioma. Anticancer Res, 2009, 29(8): 3087-3094.
49. Ruan B, Pong K, Jow F, et al. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proc Natl Acad Sci U S A, 2008, 105(1): 33-38.
50. Codeluppi S, Svensson CI, Hefferan MP, et al. The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. J Neurosci, 2009, 29(4): 1093-1104.
51. Martorell L, Gentile M, Rius J, et al. The hypoxia-inducible factor 1/NOR-1 axis regulates the survival response of endothelial cells to hypoxia. Mol Cell Biol, 2009, 29(21): 5828-5842.
  1. 1. Xiong T, Qu Y, Mu D, et al. Erythropoietin for neonatal brain injury: opportunity and challenge. Int J Dev Neurosci, 2011, 29(6): 583-591.
  2. 2. Pastor MD, Garcia-Yebenes I, Fradejas N, et al. mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J Biol Chem, 2009, 284(33): 22067-22078.
  3. 3. Yang Q, Guan KL. Expanding mTOR signaling. Cell Res, 2007, 17(8): 666-681.
  4. 4. Bilali F, Kumar P, Feerick J, et al. Hypoxia-induced hypomyelination in the developing brain is mammalian target of rapamycin-4E-binding protein-1 signaling dependent. Neuroreport, 2008, 19(6): 635-639.
  5. 5. Chen S, Atkins CM, Liu CL, et al. Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. J Cereb Blood Flow Metab, 2007, 27(5): 939-949.
  6. 6. Clarkson AN, Sutherland BA, Appleton I. The biology and pathology of hypoxia-ischemia: an update. Arch Immunol Ther Exp (Warsz), 2005, 53(3): 213-225.
  7. 7. Fahling M. Cellular oxygen sensing, signalling and how to survive translational arrest in hypoxia. Acta Physiol (Oxf), 2009, 195(2): 205-230.
  8. 8. Koh PO, Cho JH, Won CK, et al. Estradiol attenuates the focal cerebral ischemic injury through mTOR/p70S6 kinase signaling pathway. Neurosci Lett, 2008, 436(1): 62-66.
  9. 9. Chu CT. Eaten alive: autophagy and neuronal cell death after hypoxia-ischemia. Am J Pathol, 2008, 172(2): 284-287.
  10. 10. Hagberg H, Mallard C, Rousset CI, et al. Apoptotic mechanisms in the immature brain: involvement of mitochondria. J Child Neurol, 2009, 24(9): 1141-1146.
  11. 11. Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol, 2011, 69(5): 743-758.
  12. 12. Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis, 2008, 32(3): 329-339.
  13. 13. Blomgren K, Leist M, Groc L. Pathological apoptosis in the developing brain. Apoptosis, 2007, 12(5): 993-1010.
  14. 14. Deguil J, Perault-Pochat MC, Chavant F, et al. Activation of the protein p70S6K via ERK phosphorylation by cholinergic muscarinic receptors stimulation in human neuroblastoma cells and in mice brain. Toxicol Lett, 2008, 182(1-3): 91-96.
  15. 15. 陳洪菊, 屈藝, 母得志. mTOR信號通路的生物學功能. 生命的化學, 2010, 30(4): 555-561.
  16. 16. Li L, Qu Y, Li J, et al. Relationship between HIF-1α expression and neuronal apoptosis in neonatal rats with hypoxia-ischemia brain injury. Brain Res, 2007, 1180: 133-139.
  17. 17. Hanna SC, Heathcote SA, Kim WY. mTOR pathway in renal cell carcinoma. Expert Rev Anticancer Ther, 2008, 8(2): 283-292.
  18. 18. Lu DY, Liou HC, Tang CH, et al. Hypoxia-induced iNOS expression in microglia is regulated by the PI3-kinase/Akt/mTOR signaling pathway and activation of hypoxia inducible factor-1α. Biochem Pharmacol, 2006, 72(8): 992-1000.
  19. 19. Tang XD, Zhou X, Zhou KY. Dauricine inhibits insulin-like growth factor-I-induced hypoxia inducible factor 1alpha protein accumulation and vascular endothelial growth factor expression in human breast cancer cells. Acta Pharmacol Sin, 2009, 30(5): 605-616.
  20. 20. Jin X, Jin HR, Lee D, et al. A quassinoid 6alpha-tigloyloxychaparrinone inhibits hypoxia-inducible factor-1 pathway by inhibition of eukaryotic translation initiation factor 4E phosphorylation. Eur J Pharmacol, 2008, 592(1-3): 41-47.
  21. 21. Del Bufalo D, Ciuffreda L, Trisciuoglio D, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res, 2006, 66(11): 5549-5554.
  22. 22. García-Maceira P, Mateo J. Silibinin inhibits hypoxia-inducible factor-1alpha and mTOR/p70S6K/4E-BP1 signalling pathway in human cervical and hepatoma cancer cells: implications for anticancer therapy. Oncogene, 2009, 28(3): 313-324.
  23. 23. Li W, Petrimpol M, Molle KD, et al. Hypoxia-induced endothelial proliferation requires both mTORC1 and mTORC2. Circ Res, 2007, 100(1): 79-87.
  24. 24. Land SC, Tee AR. Hypoxia-inducible factor 1 alpha is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motif. J Biol Chem, 2007, 282(28): 20534-20543.
  25. 25. Wang W, Jia WD, Xu GL, et al. Antitumoral activity of rapamycin mediated through inhibition of HIF-1alpha and VEGF in hepatocellular carcinoma. Dig Dis Sci, 2009, 54(10): 2128-2136.
  26. 26. Wang Y, Zhao Q, Ma S, et al. Sirolimus inhibits human pancreatic carcinoma cell proliferation by a mechanism linked to the targeting of mTOR/HIF-1 alpha/VEGF signaling. IUBMB Life, 2007, 59(11): 717-721.
  27. 27. Humar R, Kiefer FN, Berns H, et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR) -dependent signaling. FASEB J, 2002, 16(8): 771-780.
  28. 28. Li L, Xiong Y, Qu Y, et al. The requirement of extracellular signal-related protein kinase pathway in the activation of hypoxia inducible factor 1 alpha in the developing rat brain after hypoxia-ischemia. Acta Neuropathol, 2008, 115(3): 297-303.
  29. 29. Li L, Qu Y, Mao M, et al. The involvement of phosphoinositid 3-kinase/Akt pathway in the activation of hypoxia-inducible factor-1 alpha in the developing rat brain after hypoxia-ischemia. Brain Res, 2008, 1197: 152-158.
  30. 30. Jaworski J, Sheng M. The growing role of mTOR in neuronal development and plasticity. Mol Neurobiol, 2006, 34(3): 205-219.
  31. 31. Park KK, Liu K, Hu Y, et al. PTEN/mTOR and axon regeneration. Exp Neurol, 2010, 223(1): 45-50.
  32. 32. Grider MH, Park D, Spencer DM, et al. Lipid raft-targeted Akt promotes axonal branching and growth cone expansion via mTOR and Rac1, respectively. J Neurosci Res, 2009, 87(14): 3033-3042.
  33. 33. Liu K, Lu Y, Lee JK, et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat Neurosci, 2010, 13(9): 1075-1081.
  34. 34. Fraser MM, Bayazitov IT, Zakharenko SS, et al. Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience, 2008, 151(2): 476-488.
  35. 35. Johnston MV, Ishida A, Ishida WN, et al. Plasticity and injury in the developing brain. Brain Dev, 2009, 31(1): 1-10.
  36. 36. Corsini NS, Sancho-Martinez I, Laudenklos S, et al. The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair. Cell Stem Cell, 2009, 5(2): 178-190.
  37. 37. Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell, 2009, 20(7): 1992-2003.
  38. 38. Srinivas V, Bohensky J, Shapiro IM. Autophagy: a new phase in the maturation of growth plate chondrocytes is regulated by HIF, mTOR and AMP kinase. Cells Tissues Organs, 2009, 189(1-4): 88-92.
  39. 39. Dello Russo C, Lisi L, Tringali G, et al. Involvement of mTOR kinase in cytokine-dependent microglial activation and cell proliferation. Biochem Pharmacol, 2009, 78(9): 1242-1251.
  40. 40. Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain injury. Autophagy, 2009, 5(2): 221-223.
  41. 41. Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem, 2010, 285(19): 14071-14077.
  42. 42. Shang J, Deguchi K, Yamashita T, et al. Antiapoptotic and antiautophagic effects of glial cell line-derived neurotrophic factor and hepatocyte growth factor after transient middle cerebral artery occlusion in rats. J Neurosci Res, 2010, 88(10): 2197-2206.
  43. 43. Kimura R, Okouchi M, Fujioka H, et al. Glucagon-like peptide-1 (GLP-1) protects against methylglyoxal-induced PC12 cell apoptosis through the PI3K/Akt/mTOR/GCLc/redox signaling pathway. Neuroscience, 2009, 162(4): 1212-1219.
  44. 44. Mukherjee P, Mulrooney TJ, Marsh J, et al. Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain. Mol Cancer, 2008, 7: 37.
  45. 45. Koh PO. Melatonin prevents ischemic brain injury through activation of the mTOR/p70S6 kinase signaling pathway. Neurosci Lett, 2008, 444(1): 74-78.
  46. 46. Kotulska K, Larysz-Brysz M, Grajkowska W, et al. Cardiac rhabdomyomas in tuberous sclerosis complex show apoptosis regulation and mTOR pathway abnormalities. Pediatr Dev Pathol, 2009, 12(2): 89-95.
  47. 47. Opel D, Westhoff MA, Bender A, et al. Phosphatidylinositol 3-kinase inhibition broadly sensitizes glioblastoma cells to death receptor- and drug-induced apoptosis. Cancer Res, 2008, 68(15): 6271-6280.
  48. 48. Annovazzi L, Mellai M, Caldera V, et al. mTOR, S6 and AKT expression in relation to proliferation and apoptosis/autophagy in glioma. Anticancer Res, 2009, 29(8): 3087-3094.
  49. 49. Ruan B, Pong K, Jow F, et al. Binding of rapamycin analogs to calcium channels and FKBP52 contributes to their neuroprotective activities. Proc Natl Acad Sci U S A, 2008, 105(1): 33-38.
  50. 50. Codeluppi S, Svensson CI, Hefferan MP, et al. The Rheb-mTOR pathway is upregulated in reactive astrocytes of the injured spinal cord. J Neurosci, 2009, 29(4): 1093-1104.
  51. 51. Martorell L, Gentile M, Rius J, et al. The hypoxia-inducible factor 1/NOR-1 axis regulates the survival response of endothelial cells to hypoxia. Mol Cell Biol, 2009, 29(21): 5828-5842.