. CNTF mediates the increased SVZ neurogenesis that occurs in the mouse brain after ischemic stroke. We will follow up on our finding that JNK in astrocytes represses CNTF expression and neurogenesis in nave mice, to test whether systemic treatment with JNK inhibitor can increase neurogenesis after stroke. We will also block the highly related pro-inflammatory ligand IL-6, which we found reduces stroke- induced neurogenesis, with a gp130 inhibitor. Secondly, we have discovered that blood levels of vitronectin (VTN), produced by the liver, only increase in females after stroke, and leaks into the SVZ to induce IL-6 and repress the neurogenic response. We will identify the mechanisms that regulate VTN, focusing on vagal nerve stimulated muscarinic receptors and FAK. Thirdly, we discovered in males that castration caused an unexpected and very robust effect by increasing basal levels of pro-neurogenic CNTF and decreasing detrimental IL-6, and that this was retained after MCAO. We will define the differential signaling pathways underlying this male-specific mechanism and test whether pharmacological blocking of testosterone would increase neurogenesis in males.
Aim 1 will determine whether a gp130 inhibitor promotes neurogenesis when given at 6 h or 2 months after a stroke in adult and aged mice, and whether it acts by blocking IL-6. We will also determine whether JNK inhibition would increase neurogenesis after stroke by increasing CNTF, and/or whether JNK inhibitor would further enhance the neurogenic effects of SC144 after MCAO.
Aim 2 will define potentially female-specific mechanisms that regulate liver VTN, including FAK and muscarinic acetylcholine receptors, testing pharmacological FAK inhibition and the role of the nervous system innervation of the liver after MCAO.
Aim 3 will define the signaling pathways that mediate testosterone?s effects on CNTF, LIF and IL- 6 expression in the SVZ after MCAO, and using intracerebral injection of testosterone after castration, with or without FAK, JNK, ERK or p38 inhibitors, and whether a testosterone blocker can promote neurogenesis after MCAO. These studies will build on our previous work to define novel fundamental intracellular signaling mechanisms that repress and enhance the key cytokines CNTF and IL-6 involved in SVZ neurogenesis following stroke.
This grant examines how we can stimulate the formation of new brain cells after stroke by using pharmacological drugs to increase molecules that promote neurogenesis and block those which reduce it. We will also study how we can block blood vitronectin in females and the male hormone, testosterone, in males, as they seem to play a unique detrimental role in blocking new cell formation. We expect to identify new treatments to maximize new cell formation after stroke, with different treatments for women and men, which might extend beyond to treatments of other neurological disease.
|Jia, Cuihong; Keasey, Matthew P; Malone, Hannah M et al. (2018) Vitronectin from brain pericytes promotes adult forebrain neurogenesis by stimulating CNTF. Exp Neurol 312:20-32|
|Keasey, Matthew P; Jia, Cuihong; Pimentel, Lylyan F et al. (2018) Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin-FAK and uPAR signaling. J Cell Sci 131:|
|Jia, Cuihong; Brown, Russell W; Malone, Hannah M et al. (2018) Ciliary neurotrophic factor is a key sex-specific regulator of depressive-like behavior in mice. Psychoneuroendocrinology 100:96-105|
|Banerjee, Kalpita; Keasey, Matt P; Razskazovskiy, Vladislav et al. (2017) Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells. Cell Signal 36:154-162|
|Keasey, Matthew P; Kang, Seong Su; Lovins, Chiharu et al. (2013) Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression. Cell Commun Signal 11:35|
|Kang, Seong Su; Keasey, Matthew Phillip; Hagg, Theo (2013) P2X7 receptor inhibition increases CNTF in the subventricular zone, but not neurogenesis or neuroprotection after stroke in adult mice. Transl Stroke Res 4:533-45|
|Arnold, Sheila A; Hagg, Theo (2012) Serotonin 1A receptor agonist increases species- and region-selective adult CNS proliferation, but not through CNTF. Neuropharmacology 63:1238-47|
|Kang, Seong Su; Keasey, Matthew P; Cai, Jun et al. (2012) Loss of neuron-astroglial interaction rapidly induces protective CNTF expression after stroke in mice. J Neurosci 32:9277-87|
|Kang, Seong Su; Keasey, Matthew P; Arnold, Sheila A et al. (2012) Endogenous CNTF mediates stroke-induced adult CNS neurogenesis in mice. Neurobiol Dis 49C:68-78|
|Hagg, Theo (2009) From neurotransmitters to neurotrophic factors to neurogenesis. Neuroscientist 15:20-7|
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