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. We have continue to focus on a protein with neuroprotectie properties, 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. Towards this goal, we published a paper this year describing how the C-terminal tail of the MANF protein is sufficient to confer ER localization and release of secreted protein in response to calcium depletion. In collaboration with Dr. Mart Saarma, we coauthored a paper describing the MANF knockout mouse and the role of MANF in beta cell survival in the pancreas. These data further expand our understadning of the broad protective functions of MANF. We are also preparing a manuscript describing the function of MANF in C. elegans as it relates to cellular stress, specifically, endoplasmic reticulum 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. Based on findings in our recently published MANF study, we have now published a manuscript describing how the C-terminal ASARTDL sequence of MANF can regulate protein secretion in an ER calcium-dependent manner and have filed a patent for its use as a diagnostic and therapeutic tool. Part of our current research is understanding more about the mechanisms involved in this peptide motif and trying to create proteins that are released in response to ER calcium depletion. We have collaborated with NCATS to develop a screen for drugs that affect ER calcium homeostasis. Thus far, they have screened 15,000 compounds and we have identified 30 compounds that we are following up. Our findings have great potential for developing tools to further our understanding of the relationship between ER calcium and pathogenesis, using ER Ca2+ levels to monitor disease states, and possibly regulating the release of therapeutic proteins. Our group 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.
| 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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