Neuroglobin (Ngb) is a recently discovered tissue globin found in the vertebrate brain. Initial study suggests that NGB is protective against hypoxia-ischemic insults. However, the mechanisms underlie Ngb neuroprotection remain to be defined. ? ? Our over all hypothesis is that after hypoxia/ischemia, elevated Ngb modulates neuron survival by (a) facilitating oxygen diffusion thus improving mitochondrial respiration and function, (b) scavenges neuronal nitric oxide (NO) thus reducing the formation of reactive nitrogen species (RNS) and reactive oxygen species (ROS), and (c) down-regulating cell death signaling and diminishing glutamate release. ? ? In Aim 1, we will examine the role of Ngb in regulating mitochondria respiration and neuronal death signaling after hypoxia/reoxygenation (H/R) in vitro. We hypothesize that Ngb is upregulated after H/R in mouse cerebral cortical neurons and over-expressing Ngb improves mitochondria respiration and down-regulates neuronal death signaling such as cytochrome c release and caspase activation.
In Aim 2, we will document the specific role of NO-scavenging by Ngb after H/R in vitro. Ngb will be overexpressed in neurons isolated from nNOS knockout mice and matching wild-type mice. Changes of RNS and ROS formation, mitochondrial respiration, neuronal death signaling and glutamate release will be examined and compared.
In Aim 3, we will compare Ngb overexpressing transgenic mice with wild type mice after focal cerebral ischemia in vivo. Alterations of neurological outcomes, ATP levels, RNS and ROS formations, cell death signaling, and glutamate release will be measured. To further dissect the role of Ngb in regulating neuronal NO-mediated brain damage, Ngb transgenic mice will be crossed with nNOS knockout mice. ? ? These proposed experiments should provide new insight of how Ngb protect neurons from hypoxia/ischemia and may ultimately lead to novel therapeutic strategies for the treatment of stroke. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Hicks, Ramona R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Yu, Zhanyang; Zhang, Yu; Liu, Ning et al. (2016) Roles of Neuroglobin Binding to Mitochondrial Complex III Subunit Cytochrome c1 in Oxygen-Glucose Deprivation-Induced Neurotoxicity in Primary Neurons. Mol Neurobiol 53:3249-3257
Ali, Babar; Jamal, Qazi M S; Shams, Saiba et al. (2016) In Silico Analysis of Green Tea Polyphenols as Inhibitors of AChE and BChE Enzymes in Alzheimer's Disease Treatment. CNS Neurol Disord Drug Targets 15:624-8
L, Lin; X, Wang; Z, Yu (2016) Ischemia-reperfusion Injury in the Brain: Mechanisms and Potential Therapeutic Strategies. Biochem Pharmacol (Los Angel) 5:
Liu, Ning; Yu, Zhanyang; Li, Yadan et al. (2013) Transcriptional regulation of mouse neuroglobin gene by cyclic AMP responsive element binding protein (CREB) in N2a cells. Neurosci Lett 534:333-7
Yu, Zhanyang; Poppe, Jessica L; Wang, Xiaoying (2013) Mitochondrial mechanisms of neuroglobin's neuroprotection. Oxid Med Cell Longev 2013:756989
Yu, Zhanyang; Liu, Ning; Li, Yadan et al. (2013) Neuroglobin overexpression inhibits oxygen-glucose deprivation-induced mitochondrial permeability transition pore opening in primary cultured mouse cortical neurons. Neurobiol Dis 56:95-103
Yu, Z; Xu, J; Liu, N et al. (2012) Mitochondrial distribution of neuroglobin and its response to oxygen-glucose deprivation in primary-cultured mouse cortical neurons. Neuroscience 218:235-42
Liu, Ning; Yu, Zhanyang; Xiang, Shuanglin et al. (2012) Transcriptional regulation mechanisms of hypoxia-induced neuroglobin gene expression. Biochem J 443:153-64
Yu, Z; Liu, N; Wang, Y et al. (2012) Identification of neuroglobin-interacting proteins using yeast two-hybrid screening. Neuroscience 200:99-105
Yu, Zhanyang; Liu, Ning; Liu, Jianxiang et al. (2012) Neuroglobin, a novel target for endogenous neuroprotection against stroke and neurodegenerative disorders. Int J Mol Sci 13:6995-7014

Showing the most recent 10 out of 18 publications