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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS082957-01A1
Application #
8598653
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Hicks, Ramona R
Project Start
2013-07-15
Project End
2015-06-30
Budget Start
2013-07-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$188,125
Indirect Cost
$63,125
Name
University of Wisconsin Madison
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Chandran, Raghavendar; Mehta, Suresh L; Vemuganti, Raghu (2017) Non-coding RNAs and neuroprotection after acute CNS injuries. Neurochem Int 111:12-22
Nakka, Venkata Prasuja; Prakash-Babu, Phanithi; Vemuganti, Raghu (2016) Crosstalk Between Endoplasmic Reticulum Stress, Oxidative Stress, and Autophagy: Potential Therapeutic Targets for Acute CNS Injuries. Mol Neurobiol 53:532-544
Kim, Tae-Hee; Vemuganti, Raghu (2015) Effect of sex and age interactions on functional outcome after stroke. CNS Neurosci Ther 21:327-36
Lopez, Mary S; Dempsey, Robert J; Vemuganti, Raghu (2015) Resveratrol neuroprotection in stroke and traumatic CNS injury. Neurochem Int 89:75-82
Vemuganti, Raghu; Zhao, Heng (2015) Mechanisms and therapies for acute CNS insults. Metab Brain Dis 30:353
Mehta, Suresh L; Kim, TaeHee; Vemuganti, Raghu (2015) Long Noncoding RNA FosDT Promotes Ischemic Brain Injury by Interacting with REST-Associated Chromatin-Modifying Proteins. J Neurosci 35:16443-9
Vemuganti, Raghu; Silva, Vinícius R; Mehta, Suresh L et al. (2014) Acute liver failure-induced hepatic encephalopathy s associated with changes in microRNA expression rofiles in cerebral cortex of the mouse [corrected]. Metab Brain Dis 29:891-9
Mehta, Suresh L; Dharap, Ashutosh; Vemuganti, Raghu (2014) Expression of transcribed ultraconserved regions of genome in rat cerebral cortex. Neurochem Int 77:86-93
Vemuganti, Raghu (2014) Non-coding RNAs in CNS disorders--the long and short of it. Neurochem Int 77:1
Vemuganti, Raghu; Hazell, Alan S (2014) Mechanisms of hepatic encephalopathy and thiamine deficiency. Metab Brain Dis 29:889-90