IBS patients have recurrent abdominal pain associated with altered bowel habits. The mechanisms/s of IBS is poorly understood and therapies are lacking. A compromised stress response is a key risk factors for IBS. The primary mediator of stress is the peptide cortocotropin releasing factor (CRF). In the last granting period, we have shown that in contrast to CRF1, CRF2 receptors suppress the colonic sensorimotor responses and that a compromised CRF2 function exacerbates the colonic response to stress. The mechanism how CRF2 mediates stress resiliency in the colon is not known. In preliminary data, we show that a) CRF2 activates colonic neuronal NOS and NO release and involves VIP to inhibit colonic motor response, b) human tau- overexpressing mice display altered colonic response to mild stress and c) CRF2 but not CRF1 activation suppresses stress or CRF-induced enteric and primary afferent neuronal tau phosphorylation. Based on data from last grant and the preliminary data, we hypothesize that CRF2 in the colon subserves a stress-coping function through activation of enteric NO and modulation of neuronal tau, a novel enteric stress pathway, and that altered CRF2 signaling will lead to maladaptive colonic sensorimotor responses to stress. This will be tested under three aims.
Aim 1 will determine the functional interaction of the CRF2-NO-VIP triad. CRF2 mediated molecular activation of nNOS, NO release, VIP activation and colonic contraction in vivo will be monitored in na?ve and stressed rats. Regulation of colonic CRF2 receptor splices variants under stress will be assessed to determine variants that are associated with perturbed colonic motor homeostasis Aim 2 will characterize a novel stress-tau-gut pathway and will dissect the effects and mechanism of stress-induced enteric neuronal tau modulation in rats. The identity of colonic enteric neurons with tau phophorylation, the colonic reflex and the suppression of stress-induced tau phophorylation by CRF2 will be investigated.
Aim 3 will test the hypothesis that stress or CRF-induced modulation of visceral nociception involves enteric and spinal neuronal tau phosphorylation. Myenteric and DRG neuronal tau and neuronal excitability along with visceral nocicption in stressed and non stressed rats will be assessed. Whether the CRF2 mediated suppression of visceral nociception is associated with the suppression of tau phosphorylation will be determined. Enteric and spinal tau modulation and site specific deletion of CRF2 (siRNA) will be used. Overall, the studies will use pharmacological, genetic, tissue, cellular and molecular tools to dissect the mechanisms how CRF2 receptor activation suppresses stress-related colonic sensorimotor responses. Unraveling these CRF2 mediated mechanisms in the gut response to stress will have significant impact in the understanding of stress-induced gut sensorimotor alteration and in guiding future novel therapeutic approaches to stress related diseases such as IBS.
Stress related gut diseases such as IBS affect up to 20% of the population and is among the leading causes of greater healthcare uses. Yet, there is no efficacious therapy against IBS. The proposed research is relevant to public health because, by unraveling mechanisms through which CRF2 recruits inhibitory neurotransmitters and modulates enteric neuronal tau during stress, it will help guide therapies against stress-related functional gut disorders such as IBS.
|Moussaoui, Nabila; Larauche, Muriel; Biraud, Mandy et al. (2016) Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in Male Wistar Pup Rats. PLoS One 11:e0155037|
|Duboc, H; Tolstanova, G; Yuan, P-Q et al. (2016) Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons. Neurogastroenterol Motil 28:1663-1676|
|Million, M; Larauche, M (2016) Stress, sex, and the enteric nervous system. Neurogastroenterol Motil 28:1283-9|
|Akiba, Yasutada; Kaunitz, Jonathan D; Million, Mulugeta (2015) Peripheral corticotropin-releasing factor receptor type 2 activation increases colonic blood flow through nitric oxide pathway in rats. Dig Dis Sci 60:858-67|
|TachÃ©, Yvette; Million, Mulugeta (2015) Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia. J Neurogastroenterol Motil 21:8-24|
|Mulak, Agata; Larauche, Muriel; Biraud, Mandy et al. (2015) Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice. Peptides 63:71-80|
|Vu, John P; Million, Mulugeta; Larauche, Muriel et al. (2014) Inhibition of vasoactive intestinal polypeptide (VIP) induces resistance to dextran sodium sulfate (DSS)-induced colitis in mice. J Mol Neurosci 52:37-47|
|Million, Mulugeta; Zhao, Jing-Fang; Luckey, Andrew et al. (2013) The newly developed CRF1-receptor antagonists, NGD 98-2 and NGD 9002, suppress acute stress-induced stimulation of colonic motor function and visceral hypersensitivity in rats. PLoS One 8:e73749|
|Chatzaki, Ekaterini; Anton, Peter A; Million, Mulugeta et al. (2013) Corticotropin-releasing factor receptor subtype 2 in human colonic mucosa: down-regulation in ulcerative colitis. World J Gastroenterol 19:1416-23|
|Yuan, Pu-Qing; Wu, S Vincent; Elliott, Julie et al. (2012) Expression of corticotropin releasing factor receptor type 1 (CRF1) in the human gastrointestinal tract and upregulation in the colonic mucosa in patients with ulcerative colitis. Peptides 38:62-9|
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