Targeting L-Selectin in Chronic Murine Ileitis

描述（由申请人提供）：临床研究支持粘附分子阻断（即Natalizumab）对克罗恩病（CD）的治疗效果，但导致特异性粘附分子（即整合素14）靶向的临床前数据来自结肠炎动物模型的研究。然而，60%的乳糜泻患者患有回肠炎。我们在新型小鼠回肠炎模型(即SAMP1/Yit， TNF？ARE)支持一个新概念，即到回肠末端的运输利用一组重叠但不同的分子，部分不同于那些介导到结肠的运输。在我们的模型中，删除对生理运输或归归结肠至关重要的分子（即CCR9、整合素1427或1E27）后，回肠炎的衰减不足就说明了这一点。出人意料地,肿瘤坏死因子?缺乏l -选择素或相应的负责其功能配体的硫转移酶的ARE小鼠，会发展为严重减毒的疾病。因此，我们的中心假设是l -选择素在小鼠回肠炎的发病机制中起关键作用。TNF ？ARE模型是一种独特的工具，可以识别由l -选择素缺乏介导的疾病衰减机制。我们提出了三个具体目标来进一步探索这一假设。1. 探讨l -选择素缺乏对回肠炎的免疫作用。2. 评估内皮配体在l -选择素缺乏介导的回肠炎衰减中的作用。3. 研究L-选择素缺乏的TNF中回肠炎衰减的造血决定因素？是老鼠。总的来说，这些研究有可能为T细胞如何到达小肠，诱导和维持回肠炎开辟新的视角。鉴于TNF a ARE模型和CD之间的相似性，我们的发现可能会导致新的治疗靶点。

DESCRIPTION (provided by applicant): Clinical studies support the therapeutic efficacy of adhesion molecule blockade (i.e. Natalizumab) in Crohn's disease (CD), yet the preclinical data that led to the targeting of specific adhesion molecules (i.e. integrin 14) originated from studies in animal models of colitis. However, sixty percent of patients with CD suffer from ileitis. Our work in novel murine models of ileitis (i.e. SAMP1/Yit, TNF?ARE) supports the novel concept that trafficking to the terminal ileum utilizes an overlapping yet distinct set of molecules, in part different from those that mediate traffic to the colon. This is illustrated by the lack of attenuation of ileitis seen after deletion of molecules critical for physiological trafficking or homing into the colon (i.e. CCR9, integrins 1427 or 1E27) in our model. Unexpectedly, TNF?ARE mice that lack L-selectin or the corresponding sulfotransferases responsible for its functional ligands, develop greatly attenuated disease. Thus our central hypothesis is that L-selectin is critically involved in the pathogenesis of murine ileitis. The TNF ?ARE model represents a unique tool to identify the mechanisms that underlie the attenuation of disease, mediated by L-selectin deficiency. We propose three specific aims to further explore this hypothesis. 1. Dissect the immunological effects of L-selectin deficiency in ileitis. 2. Assess the role of endothelial ligands on the attenuation of ileitis mediated by L-selectin deficiency. 3. Investigate hematopoietic determinants underlying attenuation of ileitis in L- selectin-deficient TNF ?ARE mice. Overall, these studies have the potential to open new perspectives on how T cells reach the small intestine, to induce and maintain ileitis. Given the similarities between the TNF a ARE model and CD, our findings may potentially lead to new therapeutic targets.