In the last 10-15 years, our laboratory has been investigating mechanisms of nerve cell injury or survival during conditions of O2 limitation, acute or chronic. In particular, we have focused our recent efforts on the role that membrane proteins (e.g. voltage-sensitive Na+ and KATP) play during graded hypoxia in inducing neuronal damage or preventing and delaying it. Based on preliminary data that we have recently gathered and as a result of new collaborations within the Center Grant, we have formulated hypotheses aimed at understanding the cellular and molecular mechanisms underlying the role of ionic fluxes and energy metabolism in neuronal injury during O2 and energy deprivation. Our general hypothesis is that the neuronal plasma membrane Na-dependent exchangers and their regulation are of paramount importance in determining the vulnerability to neuronal injury not only during acute but also during chronic O2 limitation. The following are our specific hypotheses: l) Na+ influx into neocortical neurons is critical for inducing hypoxic depolarization and injury during graded O2 glucose limitation and during recovery; decreasing Na+ influx protects neurons and this protection is, in part, related to presentation of high energy metabolites; 2) this Na+ influx is mediated via Na+-dependent plasma membrane exchangers (e.g. Na/H and Na/Ca; 3) neocortical neurons obtained from animals chronically exposed to low O2 postnatally are more vulnerable to acute graded O2/glucose limitation than naive neurons and that this is due to an increase in Na+ influx via up-regulated expression of exchangers and 4) the increased vulnerability in exposed neocortical neurons to O2/glucose deprivation is the result of a faster depletion of high energy metabolites caused by an increased Na+ load. Using techniques and approaches that are operative in our laboratories such as electrophysiologic, molecular biologic techniques and magnetic resonance spectroscopy, we will be able to address all 4 hypotheses. Although we realize that neuronal responsiveness to low O2 is very complex, our long term objectives are to intervene with this system In order to prolong neuronal survival or prevent nerve cell injury. We believe that these current studies are critical steps in the overall understanding of neuronal response and adaptation to short and long term stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035918-03
Application #
2858203
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Spinella, Giovanna M
Project Start
1997-01-01
Project End
2000-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gu, Xiang Q; Pamenter, Matthew E; Siemen, Detlef et al. (2014) Mitochondrial but not plasmalemmal BK channels are hypoxia-sensitive in human glioma. Glia 62:504-13
Mittal, Manish; Gu, Xiang Q; Pak, Oleg et al. (2012) Hypoxia induces Kv channel current inhibition by increased NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med 52:1033-42
Cheng, Yu; Gu, Xiang Q; Bednarczyk, Piotr et al. (2008) Hypoxia increases activity of the BK-channel in the inner mitochondrial membrane and reduces activity of the permeability transition pore. Cell Physiol Biochem 22:127-36
Gu, Xiang Q; Kanaan, Amjad; Yao, Hang et al. (2007) Chronic high-inspired CO2 decreases excitability of mouse hippocampal neurons. J Neurophysiol 97:1833-8
Gu, Xiang Q; Siemen, Detlef; Parvez, Suhel et al. (2007) Hypoxia increases BK channel activity in the inner mitochondrial membrane. Biochem Biophys Res Commun 358:311-6
Xia, Shuli; Yang, Jinghua; Su, Yingjun et al. (2005) Identification of new targets of Drosophila pre-mRNA adenosine deaminase. Physiol Genomics 20:195-202
Zhao, Peng; Xue, Jin; Gu, Xiang-Qun et al. (2005) Intermittent hypoxia modulates Na+ channel expression in developing mouse brain. Int J Dev Neurosci 23:327-33
Douglas, R M; Farahani, R; Morcillo, P et al. (2005) Hypoxia induces major effects on cell cycle kinetics and protein expression in Drosophila melanogaster embryos. Am J Physiol Regul Integr Comp Physiol 288:R511-21
Gu, Xiang Q; Xue, Jin; Haddad, Gabriel G (2004) Effect of chronically elevated CO2 on CA1 neuronal excitability. Am J Physiol Cell Physiol 287:C691-7
Douglas, R M; Xue, J; Chen, J Y et al. (2003) Chronic intermittent hypoxia decreases the expression of Na/H exchangers and HCO3-dependent transporters in mouse CNS. J Appl Physiol 95:292-9

Showing the most recent 10 out of 27 publications