ROLE OF CRF IN INTESTINAL INFLAMMATION

艰难梭菌是引起医院获得性腹泻和结肠炎的主要病原体。近年来的研究表明，神经肽参与了腹泻和肠炎的病理生理过程。神经肽促肾上腺皮质激素释放激素(CRH)是炎症反应的重要介质。CRH具有通过激活下丘脑-垂体肾上腺(HPA)轴和释放糖皮质激素而发挥的抗炎作用。此外，外周炎症部位释放的CRH具有直接的促炎作用。最近的研究结果证明CRH和HPA轴在艰难梭菌毒素A引起的肠道炎症中起着重要作用。我们将验证这样一种假设：中央型CRH通过激活HPA轴和释放糖皮质激素来抗炎，而外周型CRH通过与肠道CRH受体结合和激活特定的促炎转录因子来加剧腹泻和结肠炎症。在目标1中，我们将通过评估CRH-/-和对照组小鼠的炎症和分泌变化，并将这些变化与循环中ACTH和皮质酮的水平进行比较，来研究CRF在毒素A诱导的炎症中的作用。我们还将研究糖皮质激素不足是否改变CRH缺陷小鼠对毒素A的结肠炎反应。与Barry Wershil博士合作，我们将在体内利用CRH缺陷和肥大细胞缺陷小鼠确定CRH及其受体在肥大细胞激活中的病理生理学重要性。在目的2中，我们将鉴定CRH缺陷小鼠和正常小鼠结肠炎前后结肠中表达CRH受体的细胞，并探讨CRH受体在结肠炎发生中的功能意义。与Tor Savidge博士合作，CRH和CRH受体在人类结肠炎中的重要性也将在胎儿肠道异种移植中进行评估。在目标3中，我们将研究CRH诱导的结肠上皮细胞转录因子的激活是否参与CRH在结肠的促炎作用的中介作用。我们的研究结果将确定通过神经、内分泌和免疫系统之间的通信来控制结肠炎反应的病理生理学机制，并可能为肠道炎症的新治疗方法提供信息。

Clostridium difficile is the major causative agent of hospital-acquired diarrhea and colitis. Recent studies indicate that neuropeptides participate in the pathophysiology of diarrhea and intestinal inflammation. The neuropeptide corticotropin-releasing hormone (CRH) is an important mediator of inflammatory responses. CRH has anti-inflammatory properties exerted via activation of the hypothalamic-pituitary adrenal (HPA) axis and release of glucocorticoids. Moreover, CRH released from peripheral inflammatory sites exerts direct pro-inflammatory effects. Recent results provide evidence for an important role of CRH and the HPA axis in intestinal inflammation in response to C. difficile toxin A. We will test the hypothesis that central CRH, via activation of the HPA axis and release of glucocorticoids, exerts anti-inflammatory effects on intestinal inflammation, whereas peripheral CRH augments diarrhea and colonic inflammation via binding to intestinal CRH receptors and activation of specific pro-inflammatory transcription factors. In aim 1 we will examine the involvement of CRF in toxin A-induced inflammation by assessing inflammatory and secretory changes in CRH -/- and control mice and comparing these change with circulating levels of ACTH and corticosterone. We will also examine whether glucocorticoid insufficiency alters the colonic inflammatory responses to toxin A in CRH deficient mice. In collaboration with Dr. Barry Wershil we will determine the pathophysiologic importance of CRH and its receptors in activation of mast cells in vivo using CRH deficient and mast cell deficient mice. In aim 2 we will identify the cells in the colon the express CRH receptors in both CRH deficient and normal mice before and after colitis and examine the functional significance of CRH receptors in the development of colitis. The importance of CRH and CRH receptors in human colitis will also be evaluated in fetal intestinal xenografts in collaboration with Dr. Tor Savidge. In aim 3 we will examine whether CRH-induced activation of transcription factors in colonic epithelial cells is involved in the mediation of the pro-inflammatory effects of CRH in the colon. Results from our studies will define the pathophysiology mechanisms by which colonic inflammatory responses are controlled through communication between the nervous, endocrine, and immune system and may provide information on novel therapeutic approaches for intestinal inflammation.