As an anesthesiologist, the applicant is firmly committed to advancing academic anesthesiology through basic research. His ultimate career goal is to improve peri-operative patient care, and his immediate career goal is to create more effective and safer general anesthetics. As an assistant professor in the tenure track, Dr. Wei will receive excellent training at the University of Pennsylvania. This proposal will complete his training and provide the initial transition to becoming an independent physician-scientist. Volatile genearal anesthetics are the most common agents used for maintenance of general anesthesia, but the increasing awareness of their long lasting effects on cognition and learning suggests enhanced neurodegeneration. The overall goal of this research project is to understand whether disruption of calcium homeostasis by volatile anesthetics leads to apoptosis. The immediate goal of the study is to investigate if isoflurane and sevoflurane interact with calcium homeostasis in the endoplasmic reticulum (ER) differently, thus contributing to neuronal apoptosis in different ways. The central hypothesis is that isoflurane, but not sevoflurane, induces neuronal apoptosis via depletion of calcium in the ER. We will test several sub hypotheses via the following specific aims: (1).
Aim 1 will test that isoflurane, but not sevoflurane, induces apoptosis in both normal neurons and in a cell model of Alzheimer's disease because of its existing disruption of ER calcium. (2).
Aim 2 will test the hypothesis that Isoflurane depletes, but sevoflurane maintains or increases, ER calcium contents. (3).
Aim 3 will investigate if isoflurane and sevoflurane change the apoptosis-related Bcl-2 family proteins differently in cells. (4).
Aim 4 will test the hypothesis that Isoflurane, but not sevoflurane, decreases the Bcl-2/Bax ratio, causing neuronal degeneration at different ages, resulting in learning deficits and/or cognitive dysfunction in the rat. We will examine neuronal apoptosis by histopathology, and learning and cognition change in animals after treatment of isoflurane or sevoflurane.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM073224-05
Application #
7596179
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Cole, Alison E
Project Start
2005-05-01
Project End
2010-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
5
Fiscal Year
2009
Total Cost
$127,872
Indirect Cost
Name
University of Pennsylvania
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Xu, Z; Liu, Z; Zhang, Y et al. (2018) S100? in newborns after C-section with general vs. epidural anesthesia: a prospective observational study. Acta Anaesthesiol Scand 62:293-303
Ren, Gongyi; Zhou, Yachun; Liang, Ge et al. (2017) General Anesthetics Regulate Autophagy via Modulating the Inositol 1,4,5-Trisphosphate Receptor: Implications for Dual Effects of Cytoprotection and Cytotoxicity. Sci Rep 7:12378
Qiao, Hui; Li, Yun; Xu, Zhendong et al. (2017) Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis. Anesthesiology 127:490-501
Yang, Meirong; Wei, Huafeng (2017) Anesthetic neurotoxicity: Apoptosis and autophagic cell death mediated by calcium dysregulation. Neurotoxicol Teratol 60:59-62
Liang, Li; Wei, Huafeng (2015) Dantrolene, a treatment for Alzheimer disease? Alzheimer Dis Assoc Disord 29:1-5
Joseph, J Donald; Peng, Yi; Mak, Don-On Daniel et al. (2014) General anesthetic isoflurane modulates inositol 1,4,5-trisphosphate receptor calcium channel opening. Anesthesiology 121:528-37
Peng, Jun; Drobish, Julie K; Liang, Ge et al. (2014) Anesthetic preconditioning inhibits isoflurane-mediated apoptosis in the developing rat brain. Anesth Analg 119:939-46
Yang, Bin; Liang, Ge; Khojasteh, Soorena et al. (2014) Comparison of neurodegeneration and cognitive impairment in neonatal mice exposed to propofol or isoflurane. PLoS One 9:e99171
Zhao, Xuli; Yang, Zeyong; Liang, Ge et al. (2013) Dual effects of isoflurane on proliferation, differentiation, and survival in human neuroprogenitor cells. Anesthesiology 118:537-49
Wei, Huafeng; Inan, Saadet (2013) Dual effects of neuroprotection and neurotoxicity by general anesthetics: role of intracellular calcium homeostasis. Prog Neuropsychopharmacol Biol Psychiatry 47:156-61

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