Role and function of prohibitin in intestinal inflammation

抑制素在肠道炎症中的作用和功能

• 批准号: 8418743
• 负责人: ARIANNE L THEISS
• 金额: $ 14.65万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8418743
• 关键词: Address; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Clinical; Colitis; Data; Electrophysiology (science); Epithelial; Epithelial Cells; Epithelium; Fellowship; Functional disorder; Genes; Health; Histocompatibility Testing; Human; In Vitro; Inflammation; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Injury; Intestines; Learning; Mediating; Mitochondria; Modeling; Mus; NF-kappa B; Nuclear; Oxidative Stress; Permeability; Protein Biochemistry; Proteins; Research Design; Research Personnel; Rest; Role; Salmonella typhimurium; Signal Transduction; TNF gene; Tissues; Training; Transgenic Mice; base; cell type; cytokine; improved; in vivo; overexpression; oxidant stress; prevent; prohibitin; therapeutic target

DESCRIPTION (provided by applicant): Prohibitin is a highly conserved protein that has pleiotropic functions depending on the cell and tissue type in which it is expressed. Little is known regarding the expression and function of prohibitin in the intestine. During my postdoctoral fellowship I demonstrated that 1) prohibitin is expressed by native human colonic epithelia as well as model intestinal epithelial cells, 2) in resting intestinal epithelial cells, prohibitin localizes to the mitochondria and protects against oxidative stress, 3) prohibitin is downregulated during oxidant stress, during active human inflammatory bowel disease (IBD) and experimental colitis, and 4) prohibitin transgenic mice are protected from DSS- and Salmonella typhimurium-induced colitis and oxidative stress. In assessing the mechanism by which prohibitin modulates inflammation, our preliminary data demonstrate that prohibitin is a potent activator of Nrf2, a master transcriptional regulator that activates a battery of anti-oxidant genes. In addition, our recent in vitro data demonstrate that prohibitin inhibits TNF(-induced NF-(B activation and barrier dysfunction. Based on these data, the central hypothesis of this proposal is that prohibitin functions as an epithelial defense against oxidative stress and inflammation-induced barrier dysfunction and decreased levels of prohibitin in IBD contribute to tissue injury and inflammation. The overall objective of the proposal is to determine the mechanism underlying the protective role of prohibitin in colitis. Our interrelated yet independently achievable aims based on our hypothesis and supported by preliminary data are i) to determine the role and mechanism by which prohibitin modulates Nrf2, ii) to address the mechanism of prohibitin in inhibiting NF-(B signaling and its downstream effects, and iii) to determine the in vivo mechanism by which prohibitin ameliorates colitis Together, these studies will elucidate the function and mechanism of action of prohibitin as an activator of anti-oxidants and as an anti-inflammatory molecule in intestinal epithelial cells. The training in protein biochemistry and electrophysiology the candidate will learn from executing the proposed studies will improve potential for transition to an independent IBD researcher.

描述（由申请人提供）： 抑制素是一种高度保守的蛋白质，具有多效性功能，具体取决于其表达的细胞和组织类型。关于抑制素在肠道中的表达和功能知之甚少。在我的博士后研究期间，我证明了 1) 抑制素由天然人类结肠上皮以及模型肠上皮细胞表达，2) 在静息肠上皮细胞中，抑制素定位于线粒体并防止氧化应激，3) 抑制素在氧化应激，在活动性人类炎症性肠病 (IBD) 和实验性结肠炎期间，4) 抑制素转基因小鼠免受 DSS 和鼠伤寒沙门氏菌诱导的结肠炎和氧化应激的影响 压力。在评估抑制素调节炎症的机制时，我们的初步数据表明，抑制素是 Nrf2 的有效激活剂，Nrf2 是激活一系列抗氧化基因的主要转录调节因子。此外，我们最近的体外数据表明，抑制素可抑制 TNF(诱导的 NF-(B 激活) 和屏障功能障碍。基于这些数据，该提议的中心假设是抑制素作为上皮细胞防御氧化应激和炎症的功能。 IBD 中诱导的屏障功能障碍和抑制素水平降低会导致组织损伤和炎症。该提案的总体目标是确定抑制素在结肠炎中的保护作用的机制，这是基于我们的假设并得到支持的。初步数据是i) 确定抑制素调节 Nrf2 的作用和机制，ii) 解决抑制素抑制 NF-(B 信号传导及其下游效应的机制，以及 iii) 确定抑制素改善结肠炎的体内机制这些研究将阐明抑制素作为抗氧化剂激活剂和肠上皮细胞中抗炎分子的功能和作用机制。候选人将从执行拟议的研究中学习蛋白质生物化学和电生理学方面的培训，这将提高向独立 IBD 研究人员过渡的潜力。