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Noncoding RNAs and Post-Stroke Pathophysiology

In mammals, only <2% of the genome transcribes protein-coding RNAs (mRNAs) while >70% of the genome transcribes non-coding RNAs. A non-coding RNA is a functional RNA molecule that is not translated into a protein. Various classes of non-coding RNAs that include microRNA, long noncoding RNA (lncRNA) and piwi-interacting RNA (piRNA) are emerging as the master controllers of transcription and translation and hence dictate the normal cellular homeostasis. We are trying to understand the role of non-coding RNAs in brain damage following stroke and traumatic brain injury. Current projects are testing (a) if piRNAs altered after stroke leads to transposon dysfunction that is crucial for cell death, and (b) whether lncRNAs act as scaffolds for controlling gene expression after brain injury.      

 

MicroRNAs and Secondary Brain damage

MicroRNAs are evolutionarily conserved small non-coding RNAs that control protein translation by binding to the complimentary seed sequences in the 3’UTRs of protein-coding mRNAs. Our lab identified that stroke significantly alters microRNAome in adult brain. We are currently evaluating the role of several microRNAs in post-stroke pathophysiology. Particular projects include (a) evaluating how microRNAs and transcription factors control each other mutually after stroke, (b) deciphering the mechanism of microRNA-mediated gene induction in brain, (c) understanding the role of microRNA miR-29c in controlling DNA methylation and thus cellular homeostasis under ischemic conditions, and (d) evaluating if microRNAs control endoplasmic reticulum (ER) stress after stroke. 

 

Endoplasmic Reticulum Stress and Oxidative Stress in Neuronal Death

Efficient functioning of the 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 are currently testing if ER stress and oxidative stress are coincidental, potentiate each other bi-directionally and synergistically exacerbate the secondary brain damage after traumatic brain injury. Using a rodent model of controlled cortical impact injury, we are trying 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 eif2α, 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-trauma brain damage.  



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