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 MANF secretion is regulated by inducers of endoplasmic reticulum (ER) stress. 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 discovered a peptide sequence for regulating 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. 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. In collaboration with Dr. Yun Wang (formerly of NIDA-IRP), we evaluated the neuroregenerative properties of CART peptide in rat model of stroke and the results were published this year.

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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
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
Kim, Jung Dae; Toda, Chitoku; D'Agostino, Giuseppe et al. (2014) Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice. Proc Natl Acad Sci U S A 111:11876-81
Henderson, Mark J; Simons Wires, Emily M; Trychta, Kathleen A et al. (2014) SERCaMP: A carboxy-terminal protein modification that enables monitoring of ER calcium homeostasis. Mol Biol Cell :
Luo, Yu; Shen, Hui; Liu, Hua-Shan et al. (2013) CART peptide induces neuroregeneration in stroke rats. J Cereb Blood Flow Metab 33:300-10
Henderson, Mark J; Richie, Christopher T; Airavaara, Mikko et al. (2013) Mesencephalic astrocyte-derived neurotrophic factor (MANF) secretion and cell surface binding are modulated by KDEL receptors. J Biol Chem 288:4209-25
Sterky, Fredrik H; Pernold, Karin; Harvey, Brandon K et al. (2013) Glial cell line-derived neurotrophic factor partially ameliorates motor symptoms without slowing neurodegeneration in mice with respiratory chain-deficient dopamine neurons. Cell Transplant 22:1529-39
Harvey, Brandon K; Richie, Christopher T; Hoffer, Barry J et al. (2011) Transgenic animal models of neurodegeneration based on human genetic studies. J Neural Transm (Vienna) 118:27-45
Lim, Seung T; Airavaara, Mikko; Harvey, Brandon K (2010) Viral vectors for neurotrophic factor delivery: a gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol Res 61:14-26
Shen, Hui; Luo, Yu; Kuo, Chi-Chung et al. (2009) 9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein. J Neurosci Res 87:545-55

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