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.
| Mätlik, Kert; Anttila, Jenni E; Kuan-Yin, Tseng et al. (2018) Poststroke delivery of MANF promotes functional recovery in rats. Sci Adv 4:eaap8957 |
| Anttila, Jenni E; Albert, Katrina; Wires, Emily S et al. (2018) Post-stroke Intranasal (+)-Naloxone Delivery Reduces Microglial Activation and Improves Behavioral Recovery from Ischemic Injury. eNeuro 5: |
| Yu, Seong-Jin; Airavaara, Mikko; Wu, Kuo-Jen et al. (2017) 9-cis retinoic acid induces neurorepair in stroke brain. Sci Rep 7:4512 |
| Baldwin, Heather A; Koivula, Pyry P; Necarsulmer, Julie C et al. (2017) Step Sequence Is a Critical Gait Parameter of Unilateral 6-OHDA Parkinson's Rat Models. Cell Transplant 26:659-667 |
| Song, Kang-Ho; Fan, Alexander C; Hinkle, Joshua J et al. (2017) Microbubble gas volume: A unifying dose parameter in blood-brain barrier opening by focused ultrasound. Theranostics 7:144-152 |
| Wallace, Veronica J; Cimbro, Raffaello; Rubio, F Javier et al. (2017) Neurons Internalize Functionalized Micron-Sized Silicon Dioxide Microspheres. Cell Mol Neurobiol 37:1487-1499 |
| Koskela, Maryna; Bäck, Susanne; Võikar, Vootele et al. (2017) Update of neurotrophic factors in neurobiology of addiction and future directions. Neurobiol Dis 97:189-200 |
| Howard, Douglas B; Harvey, Brandon K (2017) Assaying the Stability and Inactivation of AAV Serotype 1 Vectors. Hum Gene Ther Methods 28:39-48 |
| Anttila, Jenni E; Whitaker, Keith W; Wires, Emily S et al. (2017) Role of microglia in ischemic focal stroke and recovery: focus on Toll-like receptors. Prog Neuropsychopharmacol Biol Psychiatry 79:3-14 |
| Wires, Emily S; Henderson, Mark J; Yan, Xiaokang et al. (2017) Longitudinal monitoring of Gaussia and Nano luciferase activities to concurrently assess ER calcium homeostasis and ER stress in vivo. PLoS One 12:e0175481 |
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