Cytoprotective Role of Heat Shock Proteins in IBD

热激蛋白在 IBD 中的细胞保护作用

• 批准号: 7915843
• 负责人: EUGENE B CHANG
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2011-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915843
• 关键词: 5' Untranslated Regions; Acute; Acute Disease; Anti-Inflammatory Agents; Anti-inflammatory; Bone Marrow; Carcinogens; Carcinoma; Cells; Chronic; Colitis; Colon Carcinoma; Cytoplasmic Granules; Development; Down-Regulation; Dysplasia; Epithelial; Epithelial Cells; Equilibrium; Gene Targeting; Genetic Translation; Heat shock proteins; Histologic; Homeostasis; Host Defense; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Inflammatory disease of the intestine; Injury; Intestinal Cancer; Intestines; Investigation; Knockout Mice; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular Genetics; Mucositis; Mucous Membrane; Mus; Mutant Strains Mice; Myeloid Cells; Natural History; Outcome; Play; Polyps; Process; Property; Regulation; Relative (related person); Resolution; Role; Stress; Transgenes; Translational Repression; base; chemical carcinogen; cytokine; immune function; in vivo; insight; methylurea; novel; prevent; protein kinase R; restoration; self-renewal; transgene expression

Intestinal homeostasis is the essential and dynamic equilibrium of factors that maintain normal mucosal function, integrity, self-renewal, and host defense. In acute diseases, the pathogenic insult is self- limited and intestinal homeostasis is restored. In inflammatory bowel diseases (IBD), intestinal homeostasis cannot be restored because of the persistence of chronic, destructive mucosal inflammation. However, less well considered is the possibility that countering mechanisms necessary for restoring intestinal homeostasis are impaired during and even after resolution of the offending insult. This proposal will therefore examine the hypothesis that the inducible heat shock protein, Hsp70, is essential for maintaining intestinal homeostasis and that its deficient expression during inflammation contributes to the development of chronic colitis and colitis-associated colon cancer. Support for this notion comes from the following observations: (1) Hsp70 has both potent cytoprotective and anti-inflammatory properties, (2) down-regulated expression of Hsp70 is observed in experimental and human colitis, rendering the mucosa more susceptible to injury and intensifying the inflammatory response, (3) gene-targeted deletion of Hsp70 transforms the otherwise, self-limited, DSS-induced colitis to a chronic, ¿IBD¿-like colitis, and (4) after AOM/DSS challenge, multi-focal, flat dysplasia-to-cancer sequence colon cancer develops in Hsp70- deficient mice as opposed to their wild-type counterparts that develop sporadic polyp-to-cancer sequence colon cancer, and 5) robust Hsp70 expression is associated with sporadic human colon cancer, but not IBD cancer. Three specific aims are proposed to investigate the role of Hsp70 (in epithelial versus immune-derived cells) in intestinal homeostasis and whether impaired expression caused by inflammation contributes to the development of chronic colitis and IBD-like colon cancer. First, we will determine if Hsp70 is essential for maintenance of intestinal homeostasis and whether it down-regulated expression in acute inflammatory and in immune-based models of colitis leads to chronic or more severe IBD-like colitis. Second, the mechanism(s) causing the observed selective translational down-regulation of Hsp70 associated with intestinal inflammation and pro-inflammatory cytokines will be defined. Finally, we will investigate whether the loss of Hsp70 expression/function is necessary and sufficient for development of spontaneous and carcinogen-induced colon cancer in mice with chronic colitis. A combination of in vitro and in vivo approaches will be employed, the latter including novel models of gene-targeted-Hsp70 deletion and epithelial- or myeloid cell-specific Hsp70 transgene expression. The insights gained through these studies will provide proof of principle that processes that impair intestinal homeostasis can contribute to the development of IBD and inflammation-associated colon cancer. Strategies to restore intestinal homeostasis would therefore be important for preventing, treating, and changing the natural history of inflammatory bowel diseases. This proposal will examine the hypothesis that the inducible heat shock protein, Hsp70, is essential for maintaining intestinal homeostasis and that its deficient expression in inflamed mucosa contributes to the development of chronic colitis and colitis-associated colon cancer. Strategies to restore Hsp70 expression in inflamed mucosa would be important for preventing, treating, and changing the natural history of inflammatory bowel diseases.

肠道稳态是维持肠道正常运转的重要因素和动态平衡 粘膜功能、完整性、自我更新和宿主防御。在急性疾病中，致病性损伤是自我攻击的。 有限且肠道稳态恢复。在炎症性肠病 (IBD) 中，肠道 由于慢性破坏性粘膜炎症的持续存在，体内平衡无法恢复。 然而，较少考虑的是恢复所需的对抗机制的可能性。 肠道稳态在问题性损伤消除期间甚至之后都会受到损害。这个提议 因此，我们将检验以下假设：诱导型热休克蛋白 Hsp70 对于 维持肠道稳态，炎症期间其表达不足会导致 慢性结肠炎和结肠炎相关结肠癌的发展。对这一观点的支持来自于 以下观察结果：(1) Hsp70 具有有效的细胞保护和抗炎特性，(2) 在实验和人类结肠炎中观察到 Hsp70 表达下调，使粘膜 更容易受到损伤并加剧炎症反应，（3）Hsp70的基因靶向删除 将 DSS 诱导的自限性结肠炎转化为慢性“IBD”样结肠炎，并且 (4) AOM/DSS 挑战，多灶性、平坦不典型增生到癌症序列结肠癌在 Hsp70 中发展- 与野生型小鼠相比，缺陷型小鼠会产生散发性息肉到癌症的序列 结肠癌，5) 强劲的 Hsp70 表达与散发性人类结肠癌相关，但不相关 炎症性肠病癌症。 提出了三个具体目标来研究 Hsp70 的作用（在上皮细胞与免疫衍生细胞中） 细胞）在肠道稳态中的作用以及炎症引起的表达受损是否有助于 慢性结肠炎和IBD样结肠癌的发展。首先，我们要确定Hsp70是否是必需的 用于维持肠道稳态及其是否在急性炎症中下调表达 在基于免疫的结肠炎模型中，会导致慢性或更严重的 IBD 样结肠炎。其次， 导致观察到的 Hsp70 选择性翻译下调的机制 将定义肠道炎症和促炎细胞因子。最后，我们将调查是否 Hsp70 表达/功能的丧失对于自发性和 致癌物诱发慢性结肠炎小鼠结肠癌。体外和体内的结合 将采用的方法，后者包括基因靶向 Hsp70 删除的新模型和 上皮细胞或骨髓细胞特异性 Hsp70 转基因表达。通过这些研究获得的见解 将提供原理证明，表明损害肠道稳态的过程可能有助于 IBD 和炎症相关结肠癌的发展。恢复肠道的策略 因此，体内平衡对于预防、治疗和改变自然史非常重要。 炎症性肠病。该提案将检验诱导热休克蛋白的假设， Hsp70 对于维持肠道稳态至关重要，其缺乏 发炎粘膜中的表达有助于慢性结肠炎的发展 结肠炎相关的结肠癌。恢复炎症中 Hsp70 表达的策略 粘膜对于预防、治疗和改变自然史非常重要 炎症性肠病。