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。 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）防止DSS和沙门氏菌伤寒诱导的结肠炎和氧化应激的固定蛋白转基因小鼠受到保护。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。 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该建议是确定禁止素在结肠炎中的保护作用的机制。通过禁止素将结肠炎同时改善结肠炎的机制，这些研究将阐明禁止素作为抗氧化剂的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。这些研究旨在提供防止毒素作为潜在治疗靶点的证据，以防止肠道炎症的后果。