Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease

Claudin-3、肠道菌群失调和炎症性肠病

基本信息

  • 批准号:
    9888859
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

Inflammatory bowel disease (IBD), consisting primarily of the ulcerative colitis (UC) and Crohn’s disease (CD), is a group of debilitating auto-immune disorders, which significantly affect one’s life-style and carry a high risk of colon cancer. While significant advances have been made in the clinical management of these diseases, the overall incidence rate and disease severity in active duty army personnel and veterans is constantly increasing possibly due to the high level of stress involved. Moreover, IBD significantly increases the risk of colon cancer, and therefore physical and economical burden of these diseases upon our veteran population is significantly high. However, the etiology of IBD remains unclear. Taken together, there is an urgent and unmet need for improved understanding of the molecular mechanisms that promote IBD susceptibility and/or disease severity, as it can help identify novel therapeutic targets. In this regard, disruption of epithelial polarity and compartmentalization, assisted by the tight junction (TJ) deregulation, plays key role in inducing and promoting mucosal inflammation. Notably, an association between the leaky gut and IBD has long been suggested. However, despite this knowledge, progress in this area for therapeutic gains has been limited due primarily to the generic perspective that proteins constituting the TJ are static and redundant in their function. This proposal disagrees with this generic view and proposes key role of claudin-3, a TJ-integral protein, in dynamic regulation of the gut epithelial and inflammatory homeostasis. Our working hypothesis is that the loss of claudin-3, which characterizes IBD patients, deregulates mucosal barrier integrity to induce gut dysbiosis and pro-inflammatory environment. Accompanying deregulations of gp130/IL6/Stat3 and Hippo/Yap signaling cascades, due to the polarity defects ensued by deregulated Par-3 expression, render chronicity to the initial inflammatory insult by deregulating mucosal injury/repair leading ultimately to neoplastic growth. This proposal is built upon a strong scientific premise as a series of studies, including ours, have now identified claudin-3 (hereon Cldn3) as a key TJ-protein in maintaining gut epithelial barrier maturity and integrity. In this regard, we found Cldn3 to be the highest expressed cell-cell adhesion protein localized primarily amongst differentiated colonocyte at the crypt top in normal colon. Furthermore, Cldn3KO mice, used to model decreased Cldn3 levels in IBD patients, exhibited hyper-permeable gut and immune cell infiltration into the lamina propria. In addition, gut dysbiosis along with specific and robust increase in gp130/IL6/Stat3 expression characterized Cldn3KO mice. Cldn3 loss also compromised colonic epithelial cell (CEC) differentiation and polarity, and promoted Hippo/Yap-signaling. Importantly, Stat-3 and Yap-signaling pathways promote hyper-proliferation, chronic inflammation and malignant growth when deregulated. Accordingly, DSS colitis-challenged Cldn3KO mice exhibited severe colitis and dysplasia (versus WT-mice). Taken together, our data support the role of Cldn3 as a rheostat in regulating the colonic epithelial and immune signaling and thereby leading to the hypothesis that Cldn3 loss is promiscuous in promoting colitis. To test our hypothesis, we propose following studies: Aim-1. To determine the expression dynamics and context for the loss of Cldn3 expression in promoting IBD; Aim-2. To determine the role and potential collaboration between IL6/Stat3 and Hippo/Yap signaling in promoting colitis under conditions of the loss of Cldn3 expression; and Aim-3. To determine the causal integration between Cldn3 loss and gut dysbiosis in promoting IBD. Overall, this proposal presents a unique platform for dissecting circuity between mucosal barrier deregulation and polarity in regulating colitis and associated cancer for therapeutic gains. Outcome will be significant in improving survival and quality of life of our Veterans.
炎症性肠病(IBD),主要包括溃疡性结肠炎(UC)和克罗恩病(CD), 是一组使人衰弱的自身免疫性疾病,严重影响一个人的生活方式, 结肠癌虽然在这些疾病的临床管理方面已经取得了重大进展, 现役军人和退伍军人的总发病率和疾病严重程度不断增加 可能是因为压力太大此外,IBD显著增加结肠癌的风险, 因此,这些疾病给我们的退伍军人带来的身体和经济负担是巨大的, 高然而,IBD的病因仍不清楚。总的来说,有一个迫切而未得到满足的需要, 提高对促进IBD易感性和/或疾病严重程度的分子机制的理解, 因为它可以帮助确定新的治疗靶点。在这方面,上皮极性的破坏和 在紧密连接(TJ)失调的辅助下,区室化在诱导和促进细胞凋亡中起关键作用。 粘膜炎症值得注意的是,肠道渗漏和IBD之间的关联早已被提出。 然而,尽管有这些知识,但在这一领域的治疗进展仍然有限,主要原因是 一般观点认为,构成TJ的蛋白质在其功能上是静态的和冗余的。这项建议 我不同意这种普遍的观点,并提出了紧密连接蛋白-3,一种TJ整合蛋白在动态调节中的关键作用 肠道上皮和炎症的稳态。我们的工作假设是claudin-3的丢失, 表征IBD患者,使粘膜屏障完整性失调以诱导肠道生态失调和促炎性 环境伴随着gp 130/IL 6/Stat 3和Hippo/雅普信号级联的失调,由于 Par-3表达失调导致的极性缺陷,使初始炎症损伤慢性化, 放松对粘膜损伤/修复的调节,最终导致肿瘤生长。 这项建议是建立在一个强大的科学前提,因为一系列的研究,包括我们的,现在已经 将claudin-3(在此为Cldn 3)鉴定为维持肠上皮屏障成熟和完整性的关键TJ蛋白。 在这方面,我们发现Cldn 3是表达最高的细胞-细胞粘附蛋白,主要定位于 在正常结肠的隐窝顶部有分化的结肠细胞。此外,用于建模的Cldn 3 KO小鼠减少了 IBD患者中的Cldn 3水平表现出高渗透性肠道和免疫细胞浸润到固有层中。 此外,肠道生态失调沿着gp 130/IL 6/Stat 3表达的特异性和稳健性增加,其特征在于 Cldn 3 KO小鼠。Cldn 3损失也损害结肠上皮细胞(CEC)分化和极性, 促进Hippo/Yap信号传导。重要的是,Stat-3和Yap信号通路促进过度增殖, 慢性炎症和恶性生长时解除管制。因此,DSS结肠炎攻击的Cldn 3 KO 小鼠表现出严重的结肠炎和发育不良(相对于WT-小鼠)。总之,我们的数据支持Cldn 3的作用, 作为调节结肠上皮和免疫信号传导的变阻器,从而导致以下假设: cldn 3丢失在促进结肠炎中是混杂的。为了验证我们的假设,我们提出了以下研究:目的-1。到 确定在促进IBD中Cldn 3表达丧失的表达动力学和背景; Aim-2.到 确定IL 6/Stat 3和Hippo/雅普信号传导在促进结肠炎中的作用和潜在协作 在Cldn 3表达丧失的条件下;和Aim-3。为了确定Cldn 3之间的因果整合, 损失和肠道生态失调促进IBD。总的来说,该提案提出了一个独特的平台,解剖电路 在调节结肠炎和相关癌症的治疗中粘膜屏障失调和极性之间的关系 收益.结果将是显着的改善生存和生活质量的退伍军人。

项目成果

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Amar B Singh其他文献

Amar B Singh的其他文献

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{{ truncateString('Amar B Singh', 18)}}的其他基金

Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease
Claudin-3、肠道菌群失调和炎症性肠病
  • 批准号:
    10455414
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Colon Tumorigenesis
Claudin-2 在结肠肿瘤发生中的作用
  • 批准号:
    9553354
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Colon Tumorigenesis
Claudin-2 在结肠肿瘤发生中的作用
  • 批准号:
    9026236
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Colon Tumorigenesis
Claudin-2 在结肠肿瘤发生中的作用
  • 批准号:
    9252978
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Claudin-3, Gut Dysbiosis and Inflammatory Bowel Disease
Claudin-3、肠道菌群失调和炎症性肠病
  • 批准号:
    10620269
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
  • 批准号:
    8187549
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
  • 批准号:
    8309950
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
  • 批准号:
    8469855
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
  • 批准号:
    8970129
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Role of Claudin-2 in Inflammatory Diseases and Colon Cancer
Claudin-2 在炎症性疾病和结肠癌中的作用
  • 批准号:
    8666745
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

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