The mechanisms that contribute to the secondary neuronal death and thereby the neurological dysfunction following stroke are not completely understood. Recent studies showed that cerebral ischemia rapidly alters the expression profiles of various classes of noncoding RNAs (ncRNAs). This observation has significant functional implications to post-stroke outcome as ncRNAs are currently considered as controllers of transcription and translation in mammals. In particular, our recent studies showed that expression of several long noncoding RNAs (lncRNAs; lincRNAs) that serve as scaffolding between chromatin-modifying proteins (CMPs), transcription factors, histones and DNA. In the present proposal, as a test case we wish to analyze the role of one such lncRNA named Fos Downstream Transcript (FosDT; MRAK159688), which is highly up-regulated in the ischemic brain. Based on the preliminary data, we hypothesize that (1) Increased FosDT expression contributes to post-stroke secondary brain damage and neurological dysfunction. (2) Mechanism of FosDT action is by its interaction with CMPs Sin3A and coREST and thereby modulating the REST-mediated suppression of GRIA2 and NFKB2 in the ischemic brain. FosDT knockdown protects brain after ischemia by de-repressing these REST-suppressed genes that prevent ischemic neuronal death.
Aim 1 is to evaluate the functional significance of FosDT in promoting secondary brain damage and neurological dysfunction following experimental stroke using FosDT siRNA-mediated knockdown.
Aim 2 is to evaluate if the mechanism of FosDT-mediated ischemic brain damage is by interaction with the REST-mediated repression of GRIA2 and NFKB2. Overall, this project will evaluate the significance of an lncRNA induced after stroke in post-ischemic brain damage and the downstream mechanisms that propagate the actions of the lncRNA after ischemia. These are the first proposed studies to our knowledge to evaluate the role of an lncRNA in post-ischemic brain damage. The long- term goal is to prioritize the experiments to decide if it is worth exploring this new class of RNAs as stroke therapeutics.

Public Health Relevance

Long noncoding RNAs (lncRNAs) are a new class of ncRNAs that are thought to modulate chromatin modifying proteins and thus transcription. The role of lncRNAs after stroke is not yet evaluated. In this proposal we will test a lncRNA upregualted after stroke to understand if that plays a role in secondary brain damage and neurological dysfunction after stroke. The long-term implications are to prioritize this new class of RNAs as stroke therapeutics.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Bosetti, Francesca
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University of Wisconsin Madison
Schools of Medicine
United States
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Morris-Blanco, Kahlilia C; Kim, TaeHee; Bertogliat, Mario J et al. (2018) Inhibition of the Epigenetic Regulator REST Ameliorates Ischemic Brain Injury. Mol Neurobiol :
Kim, Joonki; Kang, Sung-Wook; Mallilankaraman, Karthik et al. (2018) Transcriptome analysis reveals intermittent fasting-induced genetic changes in ischemic stroke. Hum Mol Genet 27:1497-1513
Mehta, Suresh L; Vemuganti, Raghu (2018) Ischemic Stroke Alters the Expression of the Transcribed Ultraconserved Regions of the Genome in Rat Brain. Stroke 49:1024-1028
Chandran, Raghavendar; Mehta, Suresh L; Vemuganti, Raghu (2017) Non-coding RNAs and neuroprotection after acute CNS injuries. Neurochem Int 111:12-22
Mehta, Suresh L; Pandi, Gopal; Vemuganti, Raghu (2017) Circular RNA Expression Profiles Alter Significantly in Mouse Brain After Transient Focal Ischemia. Stroke 48:2541-2548
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