Since their inception, volatile anesthetics have been thought to be benign inhibitors of the central nervous system. However, recent studies have seriously challenged this dogma, and caused a startling paradigm shift in the field of anesthesiology, in particular in regard to the care of infants undergoing general anesthesia. Volatile anesthetics have now been shown to cause apoptotic neuronal degeneration in developing rat brains. Preliminary data indicate that this effect is likely to exist in humans as well. As we show in our preliminary data (see Research Design), we have established a similar effect in the model organism, C. elegans. In this proposal we will identify genes responsible for the initiation of neurotoxicity following anesthetic exposure in the developing nervous systems. To accomplish this we will screen a genome wide RNAi library from the nematode, C. elegans. These genes will be tested for their ability to regulate anesthetic induced neurotoxicity. We hypothesize that significant discoveries of novel, previously unsuspected molecular targets that initiate neuronal degeneration will be identified in the nematode, and that they will be predictive of similar functionally significant responses in mammals. Available data support the belief that interactions leading to apoptosis will be maintained at a high level when studied across phylogeny. We hypothesize that identification of the genes which control anesthetic induced neurotoxicity will target molecules that can inhibit this phenomenon and guide research for safer anesthetic exposure in children.

Public Health Relevance

Volatile anesthetics have been shown to induce neurotoxicity in the central nervous system of several mammalian species, possible including humans. Little is known about how this neurotoxic effect is initiated. We propose to identify the genes important in this response using a genetic approach in the nematode, C. elegans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HD068241-02
Application #
8235788
Study Section
Special Emphasis Panel (ZRG1-CB-L (50))
Program Officer
Giacoia, George
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$243,750
Indirect Cost
$118,750
Name
Seattle Children's Hospital
Department
Type
DUNS #
048682157
City
Seattle
State
WA
Country
United States
Zip Code
98105
Gentry, Katherine R; Steele, Louise M; Sedensky, Margaret M et al. (2013) Early developmental exposure to volatile anesthetics causes behavioral defects in Caenorhabditis elegans. Anesth Analg 116:185-9