Division of Pharmacology
School of Medicine
Loma Linda University
Loma Linda, CA 92350
Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of acute mortality and chronic disability in newborns. Our laboratory is interested in identifying the cellular and molecular mechanisms of HIE. We study details of neuronal and cerebrovascular reaction to hypoxic-ischemic (HI) insult in the developing brain. The current project focuses on c-type natriuretic peptide (CNP), a potent neuropeptide released by vascular endothelial cells and neurons in various brain regions. CNP is considered as an “Angioneurin” for its dual actions in neuron survival and vascular homeostasis maintenance. We found that CNP is an innate neuroprotectant in the neonatal brain and provides cytoprotective effects to primary neuron and brain endothelial cells exposed to HI insult in vitro. Two cognate receptors NPR2 and NPR3 mediates the actions of CNP in the brain. Further studies attempt to uncover CNP and its cognate receptors-mediated signaling pathways with an emphasis on the cell-specific mechanisms in the developing brain. Moreover, we explore the potential therapeutic effect of CNP on neonatal HIE and synergized effect with hypothermia treatment. A wide range of methods is used, including animal modeling, primary neuron and endothelial cell cultures, recombinant adeno-associated virus transfection, immunohistochemistry, confocal microscopy, etc. We expect that our study can advance our understanding to the pathophysiology of neonatal HIE and provide insight into the development of new adjunct therapeutic strategies for disease treatment.
1. Tong W, Chen W, Ostrowski RP, Ma Q, Souvenir R, Zhang L, et al. Maternal hypoxia increases the activity of MMPs and decreases the expression of TIMPs in the brain of neonatal rats. Dev Neurobiol. 2010 Feb 15;70(3):182–94.
2. Chen W, Ma Q, Suzuki H, Hartman R, Tang J, Zhang JH. Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model. Stroke. 2011 Mar;42(3):764–9.
3. Ma Q, Huang B, Khatibi N, Rolland W, Suzuki H, Zhang JH, et al. PDGFR-α inhibition preserves blood-brain barrier after intracerebral hemorrhage. Ann Neurol. 2011 Dec;70(6):920–31.
4. Ma Q, Manaenko A, Khatibi NH, Chen W, Zhang JH, Tang J. Vascular adhesion protein-1 inhibition provides antiinflammatory protection after an intracerebral hemorrhagic stroke in mice. J Cereb Blood Flow Metab. 2011 Mar;31(3):881–93.
5. Chen S, Ma Q, Krafft PR, Hu Q, Rolland W, Sherchan P, et al. P2X7R/cryopyrin inflammasome axis inhibition reduces neuroinflammation after SAH. Neurobiol Dis. 2013 Oct;58:296–307.
6. Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, et al. Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun. 2013;4:2932.
7. Ma Q, Chen S, Hu Q, Feng H, Zhang JH, Tang J. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage. Ann Neurol. 2014 Feb;75(2):209–19.
8. Ma Q, Xiong F, Zhang L. Gestational hypoxia and epigenetic programming of brain development disorders. Drug Discov Today. 2014 Dec;19(12):1883–96.
9. Winkler EA, Sengillo JD, Sagare AP, Zhao Z, Ma Q, Zuniga E, et al. Blood-spinal cord barrier disruption contributes to early motor-neuron degeneration in ALS-model mice. Proc Natl Acad Sci USA. 2014 Mar 18;111(11):E1035-1042.
10. Ma Q, Zhang L. Epigenetic programming of hypoxic-ischemic encephalopathy in response to fetal hypoxia. Prog Neurobiol. 2015 Jan;124:28–48.
11. *Zhao Z, *Sagare AP, *Ma Q, Halliday MR, Kong P, Kisler K, et al. Central role for PICALM in amyloid-beta blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015 Jul;18(7):978–87.
12. *Halliday MR, *Rege SV, *Ma Q, Zhao Z, Miller CA, Winkler EA, et al. Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease. J Cereb Blood Flow Metab. 2016 Jan;36(1):216–27.
13. Li Y, Ma Q, Halavi S, Concepcion K, Hartman RE, Obenaus A, et al. Fetal stress-mediated hypomethylation increases the brain susceptibility to hypoxic-ischemic injury in neonatal rats. Exp Neurol. 2016 Jan;275 Pt 1:1–10.
14. Ma Q, Dasgupta C, Li Y, Bajwa NM, Xiong F, Harding B, et al. Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats. Neurobiol Dis. 2016 May;89:202–12.
15. Huang L, Ma Q, Li Y, Li B, Zhang L. Inhibition of microRNA-210 suppresses pro-inflammatory response and reduces acute brain injury of ischemic stroke in mice. Exp Neurol. 2017 Oct 27;300:41–50.
16. Li Y, Ma Q, Dasgupta C, Halavi S, Hartman RE, Xiao D, et al. Inhibition of DNA Methylation in the Developing Rat Brain Disrupts Sexually Dimorphic Neurobehavioral Phenotypes in Adulthood. Mol Neurobiol. 2017;54(6):3988–99.
17. Ma Q, Zhang L. C-type natriuretic peptide functions as an innate neuroprotectant in neonatal hypoxic-ischemic brain injury in mouse via natriuretic peptide receptor 2. Exp Neurol. 2018 Jun;304:58–66.
18. *Ma Q, *Zhao Z, *Sagare AP, Wu Y, Wang M, Owens NC, et al. Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism. Mol Neurodegener. 2018 19;13(1):57.
19. Ma Q, Dasgupta C, Li Y, Huang L, Zhang L. MicroRNA-210 Downregulates ISCU and Induces Mitochondrial Dysfunction and Neuronal Death in Neonatal Hypoxic-Ischemic Brain Injury. Mol Neurobiol. 2019 Jan 17;
20. Ma Q, Zhang L, Pearce WJ. MicroRNAs in brain development and cerebrovascular pathophysiology. Am J Physiol Cell Physiol. 2019 317:C3–C19.