Over the past several years, our group has been focused on studying genes with neuromodulatory, neuroprotective and/or neuroregenerative effects in models of neurodegeneration and neurotoxicity. As part of a collaboration on a primary project of Dr. Barry Hoffer (NIDA) and Mart Saarma (U Helsinki), we have examined the neuroprotective effects of conserved dopaminergic neurotrophic factor (CDNF) in an mouse model of Parkinsons disease. We have found that CDNF protein can confer neuroprotection and neuroregeneration against neurotoxicity caused by the dopaminergic neuron toxin, MPTP. The manuscript describing this study has been accepted for publication at Cell Transplantation. We are also working on the homolog to CDNF, mesencephalic astrocyted derived neurotrophic factor (MANF). We published a study last year describing the neuroprotective actions of MANF against ischemic brain injury. We are continuing to explore the neuroprotective and neuroregenerative mechanism(s) MANF/CDNF. Towards this goal, we are preparing a manuscript describing the function of MANF in C. elegans as it relates to cellular stress, specifically, endoplasmic reticulum (ER) stress. The phenomenon of ER stress occurs in many diseases beyond neurodegenerative and understanding its role may lead to broader therapeutic strategies for MANF and CDNF. In addition to our work with C. elegans, we have established several novel reagents for studying the structure/function relationship of MANF in ER stress. Using stable cell lines expressing a fusion proteins of MANF and green fluorescent protein (GFP), we have identified a region of the protein important for its localization/secretion. Using the tools weve built over the past year, we will focus on understanding MANFs function in the cell. Our section has previously demonstrated the ability of Bone Morphogenetic Protein 7 (BMP7) to promote neuroregeneration. As a continuation of this work, we have used an in vitro model of primary cortical neurons to show that BMP7 changes the appearance of axons and dendrites and have linked this to the change in extracellular matrix proteins. We are preparing the manuscript for publication. In addition to neurotrophic factors, we have completed a study examining the ability of the glutamate transporter (GLT1) to reduce the toxic effects of glutamate using an rodent model of stroke. We generated an adeno-associated vector expressing the GLT1 gene and demonstrated it could increase glutamate clearance in the brain caused by an ischemic event. This correlated with increased behavioral recovery and decreased tissue damage following ischemia. The results were published in PLoSONE and emphasize the importance of targeting ischemia-induced glutamate overflow acutely following stroke. ct is ongoing.

Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2012
Total Cost
$273,270
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
Zip Code
Marchant, Nathan J; Whitaker, Leslie R; Bossert, Jennifer M et al. (2016) Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats. Neuropsychopharmacology 41:402-9
Anttila, Jenni E; Whitaker, Keith W; Wires, Emily S et al. (2016) Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors. Prog Neuropsychopharmacol Biol Psychiatry :
Henderson, Mark J; Baldwin, Heather A; Werley, Christopher A et al. (2015) A Low Affinity GCaMP3 Variant (GCaMPer) for Imaging the Endoplasmic Reticulum Calcium Store. PLoS One 10:e0139273
Henderson, Mark J; Wires, Emily S; Trychta, Kathleen A et al. (2015) Monitoring Endoplasmic Reticulum Calcium Homeostasis Using a Gaussia Luciferase SERCaMP. J Vis Exp :
Wang, Kai; Sun, Wenzhi; Richie, Christopher T et al. (2015) Direct wavefront sensing for high-resolution in vivo imaging in scattering tissue. Nat Commun 6:7276
Lee, Chun-Ting; Bendriem, Raphael M; Kindberg, Abigail A et al. (2015) Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation. Cell Rep 10:616-32
Henriksson, Richard; Bäckman, Cristina M; Harvey, Brandon K et al. (2014) PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain. Biochim Biophys Acta 1839:1226-32
Savolainen, Mari H; Richie, Christopher T; Harvey, Brandon K et al. (2014) The beneficial effect of a prolyl oligopeptidase inhibitor, KYP-2047, on alpha-synuclein clearance and autophagy in A30P transgenic mouse. Neurobiol Dis 68:1-15
Yu, Seong-Jin; Wu, Kou-Jen; Bae, Eun K et al. (2014) Methamphetamine induces a rapid increase of intracellular Ca(++) levels in neurons overexpressing GCaMP5. Addict Biol :
Lindahl, Maria; Danilova, Tatiana; Palm, Erik et al. (2014) MANF is indispensable for the proliferation and survival of pancreatic * cells. Cell Rep 7:366-75

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