Schizophrenia is commonly recognized by its psychotic symptoms such as delusions and hallucinations, which often leads to social and functional impairment. Glutamate-NMDA neurotransmission has been strongly implicated in the genesis of schizophrenia. Recently, we have discovered that Dexrasl was found originally to bind to the Peripheral Benzodiazepine Receptor Associated Protein (PAP7), a protein of unknown function which binds to cyclic AMP dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 also binds to the Divalent Metal Transporter (DMT1), an iron import channel. We have identified a novel signaling cascade in neurons whereby stimulation of glutamate-NMDA receptors activates nNOS, leading to S-nitrosylation of Dexrasl and a physiological increase in iron uptake through DMT1. In this proposal we plan to continue extensive investigations to further define the role of Dexrasl on brain iron homeostasis and study its implications in pathophysiological conditions and mental illness. We will employ both cellular and animal models to dissect out the detailed signaling cascades and the role of individual components. We will also extend our study to the Dexrasl homologous protein, Rhes (Ras Homologous Enriched in Striatum) which is enriched in striatum and up-regulated by thyroid hormone, which is known to influence the development and the function of CMS. We will employ molecular and cellular approaches to characterize the functions and roles of Rhes in the brain. The findings from our research will improve our understandings of CNS iron homeostasis and possibly lead to development of new strategies for treatment of patients with neurological dysfunctions and mental illness.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Asanuma, Chiiko
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University of Pennsylvania
Schools of Medicine
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Chen, Yong; Bang, Sookhee; McMullen, Mary F et al. (2017) Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia. Mol Neurobiol 54:1699-1709
White, Rachel S; Bhattacharya, Anup K; Chen, Yong et al. (2016) Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1. Mol Brain 9:38
Carlson, G C; Lin, R E; Chen, Y et al. (2016) Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating. Neuroscience 322:408-15
Chen, Yong; Mathias, Lauren; Falero-Perez, Juliana M et al. (2015) PKA-mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S-nitrosylation. FEBS Lett 589:3212-9
Chen, Yong; Bang, Sookhee; Park, Soohyun et al. (2015) Acyl-CoA-binding domain containing 3 modulates NAD+ metabolism through activating poly(ADP-ribose) polymerase 1. Biochem J 469:189-98
Chen, Yong; Khan, Reas S; Cwanger, Alyssa et al. (2013) Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity. J Neurosci 33:3582-7
Choi, Bo-Ran; Bang, Sookhee; Chen, Yong et al. (2013) PKA modulates iron trafficking in the striatum via small GTPase, Rhes. Neuroscience 253:214-20
Kim, S F (2012) Animal models of eating disorders. Neuroscience 211:2-12
Bang, Sookhee; Steenstra, Catherine; Kim, Sangwon F (2012) Striatum specific protein, Rhes regulates AKT pathway. Neurosci Lett 521:142-7
Chen, Yong; Patel, Vishala; Bang, Sookhee et al. (2012) Maturation and activity of sterol regulatory element binding protein 1 is inhibited by acyl-CoA binding domain containing 3. PLoS One 7:e49906

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