Molecular Mechanisms of Estrogen Neuroprotection

Summary

Principal Investigator: Michael M Wang
Abstract: We have demonstrated that female rats experience significantly decreased brain injury after experimental stroke compared to male rats. Ovariectomy eliminates the protection from stroke injury enjoyed by female rats, suggesting that female reproductive hormones are neuroprotective. Furthermore, we have shown that exogenous estrogen is neuroprotective in multiple models of stroke. Two estrogen receptors, ER-alpha and ER-beta, act in neurons via a number of mechanisms. Estrogen receptors directly regulate gene transcription and, in addition, trigger the MAP kinase signaling cascade. The present proposal focuses on the molecular mechanism of how estrogen protects the brain from stroke. The overall hypothesize of this proposal is that estrogen protects the brain during stroke by acting upon estrogen receptors within neurons of the brain. We will use a tissue culture model of neuronal injury to address several specific questions regarding estrogen's action on neurons. In Aim 1, we will determine whether estrogen receptors are necessary for estrogen-mediated protection by examining properties of neurons in which receptors have been inactivated. In Aim 2, we will evaluate whether activation of estrogen receptor-mediated transcription is sufficient for neuroprotection by utilizing molecular mutants of ER which constitutively activate estrogen signaling. In Aim 3, we will determine whether Src/Ras/MAP kinase activation, known to occur during estrogen stimulation of neurons, plays a role in protection. In Aim 4, we will ask whether our in vitro mechanism is valid in the intact animal using viral mediated gene transfer into an in vivo model of stroke. The mechanism of how estrogen affects stroke will perhaps foster development of novel treatments for stroke, and may influence hormone replacement regimens for postmenopausal women.
Funding Period: 2001-04-20 - 2006-03-31
more information: NIH RePORT

Top Publications

  1. pmc Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e44964. 2012
  2. ncbi Sex differences in cell death
    Hong Li
    Department of Neuropathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
    Ann Neurol 58:317-21. 2005
  3. ncbi Notch3 signaling initiates choroid plexus tumor formation
    L Dang
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Oncogene 25:487-91. 2006
  4. ncbi Nucleic acid binding agents exert local toxic effects on neurites via a non-nuclear mechanism
    Sokhon Pin
    Department of Anesthesiology Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
    J Neurochem 96:1253-66. 2006
  5. ncbi Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon
    Louis Dang
    Institute for Cell Engineering, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Dev Neurosci 28:58-69. 2006
  6. pmc Conserved signal peptide of Notch3 inhibits interaction with proteasome
    Yanmei Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Biochem Biophys Res Commun 355:245-51. 2007
  7. pmc p150/glued modifies nuclear estrogen receptor function
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Mol Endocrinol 23:620-9. 2009

Detail Information

Publications7

  1. pmc Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3
    He Meng
    Department of Neurology, University of Michigan, Ann Arbor, Michigan, United States of America
    PLoS ONE 7:e44964. 2012
    ..We conclude that CADASIL mutants of NOTCH3 complex with NOTCH1, 3, and 4, slow NOTCH3 clearance, and that overexpressed wild type and mutant NOTCH3 protein interfere with key NOTCH-mediated functions in smooth muscle cells...
  2. ncbi Sex differences in cell death
    Hong Li
    Department of Neuropathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
    Ann Neurol 58:317-21. 2005
    ..These studies have relevance to researchers investigating neuroprotective agents in mixed sex experiments...
  3. ncbi Notch3 signaling initiates choroid plexus tumor formation
    L Dang
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Oncogene 25:487-91. 2006
    ..Our findings indicate that activated Notch3 can function as an oncogene in the developing brain, and link the Notch pathway to human CPT pathogenesis...
  4. ncbi Nucleic acid binding agents exert local toxic effects on neurites via a non-nuclear mechanism
    Sokhon Pin
    Department of Anesthesiology Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, USA
    J Neurochem 96:1253-66. 2006
    ..We conclude that the neurotoxic effects of nucleic acid binding compounds are mediated, at least in part, by direct neurite injury, which does not require involvement of the cell body and nucleus...
  5. ncbi Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon
    Louis Dang
    Institute for Cell Engineering, Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Dev Neurosci 28:58-69. 2006
    ..Interestingly, unlike NICD1 and NICD3, CBF1-VP16 and Hes5 did not inhibit neurosphere growth in EGF, suggesting that this effect may be mediated at least in part by CBF1/Hes-independent signaling...
  6. pmc Conserved signal peptide of Notch3 inhibits interaction with proteasome
    Yanmei Zhang
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 0622, USA
    Biochem Biophys Res Commun 355:245-51. 2007
    ..Our findings support a multifunctional role for the conserved N-terminal sequence of Notch3: targeting of the protein to the secretory pathway and reduction of cytoplasmic Notch3 expression which may inhibit cytoplasmic functions...
  7. pmc p150/glued modifies nuclear estrogen receptor function
    Soo Jung Lee
    Department of Neurology, University of Michigan, Ann Arbor, MI 48109 5622, USA
    Mol Endocrinol 23:620-9. 2009
    ..Our results suggest that p150/glued modulates estrogen sensitivity in cells through nuclear mechanisms...