Efficient functioning of the Endoplasmic reticulum (ER) is indispensable for normal cellular functions as ER plays an important role in the maintenance of intracellular Ca2+ homeostasis, proper folding of proteins, post-translation modifications and transport of nascent proteins to different destinies. Any disruption of ER results in the activation of a complex set of signaling pathways that propagate from the ER to the cytosol to the nucleus. These are collectively known as unfolded protein response (UPR), which is aimed to compensate damage and to restore the normal cellular homeostasis. While limited and transient UPR is beneficial, prolonged or severe UPR, and the ensuing ER stress leads to cell death. Furthermore, CNS insults leads to oxidative stress which is also neurotoxic. We hypothesize that following traumatic brain injury (TBI), ER stress and oxidative stress are coincidental, potentiate each other bi-directionally and synergistically exacerbate the secondary brain damage. Using a rodent model of controlled cortical impact injury, we wish to answer the following questions. (1) What is the role of PERK-mediated ER stress pathway after TBI? (2) In the post-injury brain, are ER stress and oxidative stress connected? In particular, if ER stress mediated by PERK and oxidative stress modulated by NADPH oxidase NOX2 influence each other? (3) What is the effect of knocking-out/inhibiting individual rate-limiting proteins of PERK pathway eif2?, ATF4 and CHOP on oxidative stress and neuronal damage after TBI? Conversely, what is the effect of knocking-out/inhibiting NOX2 on ER stress and neuronal damage after TBI? The long-term goal is to understand the mutual interplay of ER stress and oxidative stress in post-TBI brain damage.

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We wish to test the significance and mutual interplay of Endoplasmic Reticulum stress and oxidative stress following traumatic brain injury. The ultimate goal is to understand the mechanism that promoter secondary brain damage after brain trauma.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Acute Neural Injury and Epilepsy Study Section (ANIE)
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Bellgowan, Patrick S F
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University of Wisconsin Madison
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United States
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Vemuganti, Raghu; Zhao, Heng (2015) Mechanisms and therapies for acute CNS insults. Metab Brain Dis 30:353
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Vemuganti, Raghu (2014) Non-coding RNAs in CNS disorders--the long and short of it. Neurochem Int 77:1
Mehta, Suresh L; Dharap, Ashutosh; Vemuganti, Raghu (2014) Expression of transcribed ultraconserved regions of genome in rat cerebral cortex. Neurochem Int 77:86-93