Modulation of Colonic Response to Stress by Peripheral CRF2 Receptors

外周 CRF2 受体调节结肠对应激的反应

• 批准号: 9116211
• 负责人: MILLION MULUGETA
• 金额: $ 26.28万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116211
• 关键词: Abdominal Pain; Acute; Affect; Biology; CRF receptor type 1; CRF receptor type 2; Chemicals; Chronic; Chronic stress; Code; Colon; Colorectal; Data; Disease; Enteral; Failure; Functional disorder; Future; G-Protein-Coupled Receptors; Gene Expression; Gene Silencing; Genetic; Grant; Habits; Health; Healthcare; Homeostasis; Human; Intestines; Irritable Bowel Syndrome; Knockout Mice; Lead; Measurement; Mediating; Mediator of activation protein; Medical; Modeling; Molecular; Monitor; Motor; Motor Pathways; Mus; Neurons; Neurotransmitters; Nitric Oxide; Nitric Oxide Synthase Type I; Nociception; Pain; Pathway interactions; Patients; Peptides; Peripheral; Population; Proto-Oncogene Proteins c-akt; Public Health; RNA Interference; RNA Splicing; Rattus; Receptor Activation; Receptor Gene; Recruitment Activity; Recurrence; Reflex action; Regulation; Research; Risk Factors; Rodent; Sensory; Signal Transduction; Site; Small Interfering RNA; Spinal; Spinal Cord; Stress; Stress and Coping; System; Taxes; Testing; Time; Tissues; Transgenic Mice; Triad Acrylic Resin; Untranslated RNA; Variant; Visceral; base; biological adaptation to stress; coping; coping mechanism; in vivo; neuronal excitability; novel; novel therapeutic intervention; overexpression; pressure; receptor; release factor; response; sensor; stressor; targeted therapy trials; tau Proteins; tau phosphorylation; tool

DESCRIPTION (provided by applicant): IBS patients have recurrent abdominal pain associated with altered bowel habits. The mechanisms of IBS are 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 naive 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.

描述（由申请人提供）：IBS患者患有与肠习惯改变有关的腹痛复发。 IBS的机制知之甚少，缺乏疗法。压力反应受损是IBS的关键风险因素。应激的主要介体是肽皮质激素释放因子（CRF）。在最后给予期间，我们表明，与CRF1相比，CRF2受体抑制了结肠感觉运动反应，而受损的CRF2功能加剧了对压力的结肠反应。 CRF2如何介导结肠中的应激弹性的机制尚不清楚。在初步数据中，我们表明a）CRF2激活了结肠神经元的NOS，无释放并涉及VIP抑制结肠运动反应，b）人tau-过表达的小鼠表现出对轻度压力的结肠反应改变，C）CRF2，但不能抑制压力抑制压力或CRF诱导的肠或原发性抗衰老神经元tause tausal tauslation。基于上次赠款和初步数据的数据，我们假设结肠中的CRF2通过激活肠NO和Neuronal Tau的调节（一种新型的肠应力途径），这是一种应力培养功能，这是一种新型的肠应力途径，并且CRF2信号的改变将导致不良的接触型肠内感染者对压力的不良反应。这将根据三个目标进行测试。 AIM 1将确定CRF2-NO-VIP三合会的功能相互作用。 CRF2介导的NNOS分子激活，无释放，VIP激活和体内的结肠收缩将在天真和压力大鼠中受到监测。将评估应力下的结肠CRF2受体剪接变体的调节，以确定与扰动的结肠运动稳态相关的变体AIM 2将表征一种新型的应激 - 抗tau-gut途径，并将剖析应力诱导的大鼠肠诱导的肠神经元调节的作用和机制。将研究CRF2的结肠肠神经元与tau噬菌体，结肠反射和抑制压力诱导的tau噬菌体的身份。 AIM 3将检验以下假设：应激或CRF诱导的内脏伤害感受涉及肠和脊髓神经元TAU磷酸化。将评估肌和DRG神经元tau和神经元兴奋性，以及应力和无压力大鼠的内脏伤害。 CRF2介导的内脏伤害感受抑制是否与抑制Tau磷酸化有关。将使用CRF2（siRNA）的肠和脊柱TAU调制以及位点特异性缺失。总体而言，研究将使用药理学，遗传，组织，细胞和分子工具来剖定CRF2受体激活如何抑制与压力相关的结肠感觉运动反应的机制。在肠道响应中阐明这些CRF2介导的机制将对理解压力诱导的肠道感觉运动改变以及指导未来的新型治疗方法来对应激相关疾病（例如IBS）产生重大影响。