172-Estradiol (E2) has been implicated to exert neuroprotection in a variety of neurodegenerative disorders, including stroke;however, the mechanisms underlying its nongenomic and genomic signaling in the brain, and its neuroprotective effects remains unclear. Work by our group may shed light on this issue via our cloning of a novel ER coregulator, called PELP1, which we propose is the critical """"""""missing link"""""""" that explains E2 ability to induce both nongenomic and genomic signaling in the brain and neuroprotection. To test our hypothesis, Aim 1 would use a PELP1 forebrain-specific KO (PELP1 FB KO) mouse model to determine the role of PELP1 in E2 nongenomic and genomic signaling, antioxidant actions, and neuroprotective effects in the brain following cerebral ischemia. Since little is known about the regulation of PELP1 in the brain, Aim 2 would characterize PELP1 expression, phosphorylation and signalsome formation in the brain following cerebral ischemia, determine the regulatory role of E2, and identify kinases responsible for the phosphorylation of PELP1. Preliminary data suggest that PELP1 may also play an important role in regulating local E2 production in the brain by regulating activation of the brain aromatase promoter. Thus, Aim 3 would examine the effect of PELP1 knockout on basal and E2-induced aromatase expression and activity in the brain through use of PELP1 FB KO mice, and identify the specific brain aromatase promoter regulated by PELP1. Recruitment of PELP1 to the brain aromatase promoter would also be assessed by ChIP, and the potential role of local E2 production in amplifying neuroprotection by low physiological levels of E2 would also be examined. Finally, Aim 4 would test the hypothesis that loss of E2 neuroprotective ability after a period of long-term E2 deprivation (such as occurs after menopause) is due to a brain-specific epigenetic gene silencing of PELP1 and/or ER1, and would determine whether the gene silencing is reversible and whether E2 sensitivity can be reinstated in the brain. The proposed studies have the potential to significantly advance our understanding of how E2 exerts its signaling and neuroprotective effects in the brain, and may provide a mechanistic understanding of why E2 failed to exert beneficial cardiovascular and neural effects in the WHI study, where E2 replacement was begun long after the onset of menopause.

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Estrogen (E2) has been implicated to exert neuroprotection in a variety of neurodegenerative disorders, including stroke. This proposal would elucidate the mechanisms underlying E2 neuroprotection in the brain and potentially provide a mechanistic explanation as to why the Women's'Health Initiative (WHI) studies failed to observe beneficial effect of E2.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Koenig, James I
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Georgia Regents University
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Thakkar, Roshni; Wang, Ruimin; Sareddy, Gangadhara et al. (2016) NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17β-Estradiol. Oxid Med Cell Longev 2016:8309031
Sareddy, Gangadhara R; Zhang, Quanguang; Wang, Ruimin et al. (2015) Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain. Proc Natl Acad Sci U S A 112:E6673-82
Tu, Jingyi; Zhang, Xi; Zhu, Ying et al. (2015) Cell-Permeable Peptide Targeting the Nrf2-Keap1 Interaction: A Potential Novel Therapy for Global Cerebral Ischemia. J Neurosci 35:14727-39
Khan, Mohammad M; Wakade, Chandramohan; de Sevilla, Liesl et al. (2015) Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia. J Steroid Biochem Mol Biol 146:38-47
Nair, B C; Krishnan, S R; Sareddy, G R et al. (2014) Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response. Cell Death Differ 21:1409-18
Mann, Monica; Zou, Yi; Chen, Yidong et al. (2014) PELP1 oncogenic functions involve alternative splicing via PRMT6. Mol Oncol 8:389-400
Tang, Hui; Zhang, Quanguang; Yang, Licai et al. (2014) GPR30 mediates estrogen rapid signaling and neuroprotection. Mol Cell Endocrinol 387:52-8
Scott, Erin L; Zhang, Quan-Guang; Vadlamudi, Ratna K et al. (2014) Premature menopause and risk of neurological disease: basic mechanisms and clinical implications. Mol Cell Endocrinol 389:2-6
Zhang, Quan-Guang; Wang, Ruimin; Tang, Hui et al. (2014) Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus. Mol Cell Endocrinol 389:84-91
Khan, Mohammad M; Dhandapani, Krishnan M; Zhang, Quan-Guang et al. (2013) Estrogen regulation of spine density and excitatory synapses in rat prefrontal and somatosensory cerebral cortex. Steroids 78:614-23

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