Project Details
Abstract
A brief yet complete disruption of blood flow to the brain, or “transient global ischemia (TGI)”,
may cause delayed neuronal death in hippocampus. This neuronal death occurs 2-4 d after TGI
within a specific neuronal population of hippocampus, namely the CA1 pyramidal neurons.
Clinically, TGI occurs in such serious cardiovascular disorders as cardiogenic shock after
myocardial infarction or reversible severe hypotension. The underlying mechanisms of delayed
CA1 neuronal loss following TGI are not well understood. Cerebral ischemia can cause
excessive reactive oxygen species (ROS) generation and result in neuronal damage. Recent
studies suggest that sestrin2 is a crucial regulator for ROS scavenging enzymes such as
peroxiredoxins. Also, it was revealed that sestrin2 may regulate autophagy and protein
synthesis related-translation machinery through the effect of mammalian target of
rapamycin complex1 (mTORC1) and may have a pivotal for longevitity. It is thus reasonable to
assume that sestrin2 signaling may act as an endogenous protective response, regulate ROS
formation, accommodate cell metabolism to survive and would be vital to lessen TGI-induced
neuronal injury. However, the role of sestrin2 in cerebral ischemia is not well studied. In this
project, we attempt to define a novel protective pathway involving sestrin2 signaling which
may regulate the autophagy and protein synthesis through the effect of mTORC1 in
TGI-induced neuronal damage in hippocampus. Three specific aims will be tested. We’ll first
determine if TGI-induced neuronal damage in hippocampus may relate to excessive ROS
formation and concomitantly induce the change of sestrin2, mTORC1 , autophagy and
protein synthetic machinery. Secondly, we’ll determine the causal relationship in this
endogenous protective pathway among sestrin2/mTORC1 and related molecules involving
autophagy and protein synthesis. Thirdly, we’ll determine if sestirn2 signaling is involving the
underlying mechanisms in some medications possessing neuroprotective effects such as
thiazolidinedione drugs, stains and minocycline. These aims will be accomplished by using rat
TGI model and investigating sestrin2 and mTORC1 activity with immunoblotting and
imunohistochemistry study. The detrimental effect of excessive ROS generation will be
measured with protein carbonyl, malondialdehyde, 8-OH-dG for protein, lipid and DNA
damage respectively. The outcome measurement will include the extent of DNA
fragmentation and neuronal count by cresyl violet staining in hippocampal CA1 subfield. We’ll
use pharmacological and molecular approaches with inhibitors and siRNA for sestrin2 to
validate this signaling pathway. Several commonly used medications including pioglitazine,
rosuvastatin and minocycline with neuroprotective effects may have direct or indirect
mechanisms involving induction of sestirn2 and worth to explore. The ultimate goal of this
project is to develop protective strategies and prevent TGI-induced neuronal injury in
hippocampus via modulation of the sestrin2/mTORC1 signaling pathways, regulating
autophagy and protein synthesis and hence lessening ROS formation and adapting cell
metabolism to survive. The ability to reduce TGI-induced neuronal injury in hippocampus may
have therapeutic implication not only in TGI but also in other stroke syndromes.
Project IDs
Project ID:PC10401-1143
External Project ID:MOST103-2314-B182-026-MY2
External Project ID:MOST103-2314-B182-026-MY2
Status | Finished |
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Effective start/end date | 01/08/15 → 31/07/16 |
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