miRNAs and PPAR-gamma-induced neuroprotection

Summary

Principal Investigator: Raghu Vemuganti
Abstract: DESCRIPTION (provided by applicant): 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[unreadable] 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.
Funding Period: 2012-07-01 - 2014-06-30
more information: NIH RePORT

Top Publications

  1. pmc MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage
    Gopal Pandi
    Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
    PLoS ONE 8:e58039. 2013
  2. pmc All's well that transcribes well: non-coding RNAs and post-stroke brain damage
    Raghu Vemuganti
    Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA Electronic address
    Neurochem Int 63:438-49. 2013
  3. pmc Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST
    Ashutosh Dharap
    Department of Neurological Surgery, University of Wisconsin, Madison, WI, U S A
    ASN Neuro 5:283-9. 2013
  4. pmc microRNA-100 targets SMRT/NCOR2, reduces proliferation, and improves survival in glioblastoma animal models
    Bahauddeen M Alrfaei
    Department of Neurological Surgery and Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
    PLoS ONE 8:e80865. 2013

Detail Information

Publications4

  1. pmc MicroRNA miR-29c down-regulation leading to de-repression of its target DNA methyltransferase 3a promotes ischemic brain damage
    Gopal Pandi
    Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA
    PLoS ONE 8:e58039. 2013
    ..Furthermore, REST is an upstream transcriptional controller of miR-29c and curtailing REST induction prevents miR-29c down-regulation and ischemic neuronal death...
  2. pmc All's well that transcribes well: non-coding RNAs and post-stroke brain damage
    Raghu Vemuganti
    Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA Electronic address
    Neurochem Int 63:438-49. 2013
    ..These studies are of interest for therapeutic development as they may contribute to identifying new ncRNA targets that can be modulated to prevent secondary brain damage after stroke. ..
  3. pmc Increased binding of stroke-induced long non-coding RNAs to the transcriptional corepressors Sin3A and coREST
    Ashutosh Dharap
    Department of Neurological Surgery, University of Wisconsin, Madison, WI, U S A
    ASN Neuro 5:283-9. 2013
    ..This is the first study to show that stroke-induced lncRNAs might associate with CMPs to modulate the post-ischemic epigenetic landscape. ..
  4. pmc microRNA-100 targets SMRT/NCOR2, reduces proliferation, and improves survival in glioblastoma animal models
    Bahauddeen M Alrfaei
    Department of Neurological Surgery and Cellular and Molecular Pathology Training Program, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America
    PLoS ONE 8:e80865. 2013
    ..01; n=8). These studies establish miR-100's effect on tumor GBM growth, and suggest clinical potential for microRNA-related GBM therapy. ..

Research Grants30

  1. The role of smooth muscle PPAR gamma in neointima formation
    SETH BERNAT FURGESON; Fiscal Year: 2013
    ..In Aim Three, we will determine which agent can reduce neointima size the greatest after wire injury. ..
  2. Novel Mechanisms of Smooth Muscle Beta2-receptor Regulation Relevant to Asthma
    Deepak A Deshpande; Fiscal Year: 2013
    ..Taken together, these proposed studies will combine molecular, cellular and transgenic approaches to define mechanisms of [unreadable]2AR function and regulation relevant to asthma. ..
  3. Mechanism of Renal Cell Injury in Diabetes
    Goutam Ghosh Choudhury; Fiscal Year: 2013
    ....
  4. Structural and functional consequences of disease SNPs on the transcriptome
    ALAIN T LAEDERACH; Fiscal Year: 2013
    ..We are fundamentally interested in understanding the structural consequences of common genetic variation on the function of the transcriptome. ..
  5. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  6. Molecular Analyses and Interventions for Biodefense and Emerging Pathogens
    Olaf Schneewind; Fiscal Year: 2013
    ..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..