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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS079585-02
Application #
8465931
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Bosetti, Francesca
Project Start
2012-07-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$217,849
Indirect Cost
$73,099
Name
University of Wisconsin Madison
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Vemuganti, Raghu; Zhao, Heng (2015) Mechanisms and therapies for acute CNS insults. Metab Brain Dis 30:353
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; Hazell, Alan S (2014) Mechanisms of hepatic encephalopathy and thiamine deficiency. Metab Brain Dis 29:889-90
Vemuganti, Raghu (2014) Non-coding RNAs in CNS disorders--the long and short of it. Neurochem Int 77:1
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
Dharap, Ashutosh; Pokrzywa, Courtney; Vemuganti, Raghu (2013) Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST. ASN Neuro 5:283-9
Vemuganti, Raghu (2013) All's well that transcribes well: non-coding RNAs and post-stroke brain damage. Neurochem Int 63:438-49
Pandi, Gopal; Nakka, Venkata P; Dharap, Ashutosh et al. (2013) MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage. PLoS One 8:e58039