CONTRACTILE SIGNAL TRANSDUCTION IN ULCERATIVE COLITIS

描述（由申请人提供）：溃疡性结肠炎是一种影响大肠的慢性炎症性疾病，虽然最常见于直肠乙状体区，但也可能累及整个结肠。溃疡性结肠炎的炎症在组织学上局限于粘膜，其作用在表层比在深层如固有肌层更明显。然而，炎症可能会影响肌肉层，导致运动功能障碍，从而导致关键的临床症状，包括腹泻、便秘和绞痛。为了定义炎症和运动功能的相关改变，我们将检查来自活动性溃疡性结肠炎患者的乙状结肠的圆形肌肉，并将其与来自癌症切除的组织学正常结肠组织的无病边缘的肌肉进行比较。乙状结肠最常受累并常被切除，这避免了与疾病不同解剖位置相关的变异。在初步实验中，我们发现炎症介质如白细胞介素-1 β和过氧化氢存在于固有肌层中。我们的中心假设是，炎症介质首先由粘膜中的炎症细胞产生，可能诱导靶细胞本身产生额外的介质，并且随着时间的推移，固有肌层受到影响，导致运动障碍。因此，我们建议：A)定义炎症诱导的人类乙状结肠收缩信号转导通路的变化。B)测试已知存在于溃疡性结肠炎粘膜中的选定炎症介质的作用，以确定它们对观察到的结肠运动功能变化的个体贡献。C)确定抑制选定的炎症介质是否可以逆转炎症介导的结肠运动功能改变。研究炎症机制与运动功能变化之间的关系可能有助于理解溃疡性结肠炎相关的功能障碍，并确定治疗干预的新靶点。

DESCRIPTION (provided by applicant): Ulcerative colitis is a chronic inflammatory condition affecting the large bowel: Although it is most frequent in the rectosigrnoid area, it may involve the whole colon. Inflammation in ulcerative colitis is histologically limited to the mucosa, and its effects have been better characterized in the superficial than in the deeper layers such as muscularis propria. Inflammation, however, may affect the muscle layer, leading to motor dysfunction, which contributes to key clinical symptoms, including diarrhea, constipation, and crampy abdominal pain. To define inflammation, associated changes in motor function we will examine the circular muscle from the sigmoid colon from patient with active ulcerative colitis and compare it with muscle from disease-free margins of histologically normal colon tissue from cancer resections. The sigmoid is most often involved and frequently resected, and this avoids variations associated with different anatomical locations of the disease. In preliminary experiments, we find that inflammatory mediators such as interleukin-1beta and hydrogen peroxide are present in the muscularis propria. Our central hypothesis is that inflammatory mediators, first produced by inflammatory cells in the mucosa, may induce production of additional mediators by the target cells themselves, and that in time the muscularis propria becomes affected leading to motor disturbances. We therefore propose to: A) Define inflammation-induced changes in contractile signal transduction pathways of human sigmoid colon. B) Test the effect of selected inflammatory mediators, known to be present in ulcerative colitis mucosa, to determine their individual contribution to the observed changes in colonic motor function. C) Determine whether inhibition of selected inflammatory mediators may reverse inflammation-mediated changes in colonic motor function. Examining the relationship between inflammatory mechanisms and changes in motor function may help in understanding the functional disturbances associated with ulcerative colitis and identifying new targets for therapeutic intervention.