The miRNAs are transcribed as primary miRNAs (primiRs) by RNA polymerase II from either independent miRNA genes or from the introns of protein-coding genes. The miRNA gene promoters are known to contain many transcription factor binding sites, but the role of transcription factors in miRNA biogenesis is not yet understood. We made an in silico observation that the promoters of certain miRNAs contain binding sites for the transcription factor PPAR? known as PPREs. Preliminary studies showed that several miRNAs that contain PPREs in their promoters were induced by PPAR? agonist rosiglitazone indicating that PPAR? might control the expression of miRNAs. In addition to targeting 3'-UTRs of mRNAs to repress translation, the miRNAs can also bind to the promoters of protein-coding genes in a sequence-specific manner. With bioinformatics, we observed binding sites for 4 miRNAs in PPAR? promoter indicating that those miRNAs might control PPAR? gene expression. Interestingly, PPAR? promoter contains binding sites for miRNAs that have PPREs in their promoters. For example, promoters of mir-329 and miR-145 showed 4 PPREs each while PPAR? promoter showed binding site for both miR-329 and miR-145. We hypothesize that PPAR? and specific miRNAs modulate each other with significant consequences in maintaining cellular equilibrium. Furthermore, some of the pleiotropic neuroprotective effects of PPAR? agonists might be due to their effect on miRNAs.
Aim 1 is to test if PPAR? activation alters the expression of PPRE-containing miRNAs and to study if PPAR? down-stream miRNAs play a role in PPAR-mediated neuroprotection.
Aim 2 is to test if specific miRNAs can induce PPAR? expression by promoter interaction and if that can potentiate the neuroprotection afforded by PPAR? agonists. The overall goal is to study if PPAR? is in a cyclical loop with certain miRNA and their mutual inducibility has functional significance.

Public Health Relevance

Transcription factors and microRNAs are master controllers of gene and protein expression. This proposal wishes to evaluate the mutual interaction and the subsequent consequences of a transcription factor known as PPAR with certain miRNAs in mediating neuroprotection after ischemia.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Bosetti, Francesca
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University of Wisconsin Madison
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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
Dharap, Ashutosh; Pokrzywa, Courtney; Murali, Shruthi et al. (2015) Mutual induction of transcription factor PPAR? and microRNAs miR-145 and miR-329. J Neurochem 135:139-46
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
Alrfaei, Bahauddeen M; Vemuganti, Raghu; Kuo, John S (2013) microRNA-100 targets SMRT/NCOR2, reduces proliferation, and improves survival in glioblastoma animal models. PLoS One 8:e80865

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