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: 8222138
• 负责人: ARIANNE L THEISS
• 金额: $ 4.82万
• 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/8222138
• 关键词: Role; function; prohibitin; intestinal; inflammation

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. PUBLIC HEALTH RELEVANCE: This study proposes to define the function and mechanism of prohibitin in protecting against oxidative stress, NF-(B activation and barrier dysfunction, which are hallmarks of intestinal inflammation. These studies are designed to provide evidence for prohibitin as a potential therapeutic target to prevent the consequences of intestinal inflammation.

描述（由申请人提供）： 禁止素是一种高度保守的蛋白质，它具有表达的细胞和组织类型，具有多效性功能。关于禁止素在肠道中的表达和功能知之甚少。在我的博士后奖学金中，我证明了1）抗肠上皮细胞和模型肠上皮细胞表达禁止素，2）在静止的肠上皮细胞中，禁止在线粒体上定位于线粒体，并预防氧化应激，3）蛋白质降低，3）蛋白质下降，3）蛋白质蛋白质。氧化剂应激，在活性的人类炎症性肠病（IBD）和实验性结肠炎以及4）防止肽的转基因小鼠受到DSS和伤寒沙门氏菌诱导的结肠炎和氧化应激的保护。在评估禁止炎症的机制时，我们的初步数据表明，禁止素是NRF2的有效激活剂，NRF2是一种激活一系列抗氧化基因的主转录调节剂。此外，我们最近的体外数据表明，禁止毒素抑制TNF（诱导的NF-（B激活和屏障功能障碍。基于这些数据，该提案的中心假设是，预防素的作用是抗氧化应激和炎症 - 炎症 - 诱导的屏障功能障碍和IBD中的降低水平有助于组织损伤和炎症。初步数据是i）确定禁止蛋白调节NRF2的作用和机制，ii）解决抑制NF-（B信号传导及其下游效应的机制，以及III）的机制，以确定体内机制，从而阻止这种机制。结肠炎，这些研究将阐明禁止素作为抗氧化剂活化剂的作用和机理，并在肠上皮细胞中作为抗炎分子。蛋白质生物化学和电生理学的培训候选人将从执行拟议的研究中学习，将提高过渡到独立的IBD研究人员的潜力。 公共卫生相关性： 这项研究建议定义防止氧化应激的功能和机制，NF-（B激活和屏障功能障碍，它们是肠炎的标志。这些研究旨在提供预防素作为防止治疗靶标的证据肠炎的后果。