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: 7462051
• 负责人: EUGENE B CHANG
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7462051
• 关键词: 5' Untranslated Regions; Acute; Acute Disease; Anti-Inflammatory Agents; Anti-inflammatory; Bone Marrow; Carcinogens; Carcinoma; Cells; Chronic; Colitis; Colon Carcinoma; Condition; 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; Public Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.

描述（由申请人提供）：肠道稳态是维持正常粘膜功能、完整性、自我更新和宿主防御的因子的基本动态平衡。在急性疾病中，致病性损伤是自限性的，并且肠道内稳态得以恢复。在炎症性肠道疾病（IBD）中，由于慢性、破坏性粘膜炎症的持续存在，肠道稳态无法恢复。然而，较少考虑的可能性是，恢复肠道内稳态所需的对抗机制在冒犯性损伤期间甚至在解决之后受损。因此，本提案将研究的假设，诱导热休克蛋白，热休克蛋白70，是必不可少的维持肠道内环境的平衡，其表达不足，在炎症过程中有助于慢性结肠炎和结肠炎相关的结肠癌的发展。以下意见支持这一观点：（1）Hsp 70具有有效的细胞保护和抗炎特性，（2）在实验性和人结肠炎中观察到Hsp 70的下调表达，使粘膜更易受损伤并增强炎症反应，（3）Hsp 70的基因靶向缺失将原本自限性DSS诱导的结肠炎转变为慢性，IBD样结肠炎，和（4）在AOM/DSS攻击后，多灶性扁平发育异常-癌症序列结肠癌在Hsp 70缺陷小鼠中发展，与其发展散发性息肉-癌症序列结肠癌的野生型对应物相反，和5）稳健的Hsp 70表达与散发性人结肠癌相关，但与IBD癌无关。提出了三个具体的目标，以调查的作用，热休克蛋白70（上皮细胞与免疫源性细胞）在肠道内稳态，以及是否受损的表达引起的炎症导致的慢性结肠炎和IBD样结肠癌的发展。首先，我们将确定Hsp 70是否对维持肠道内稳态至关重要，以及它是否在急性炎症和基于免疫的结肠炎模型中下调表达，导致慢性或更严重的IBD样结肠炎。其次，将确定引起所观察到的与肠道炎症和促炎细胞因子相关的Hsp 70的选择性翻译下调的机制。最后，我们将调查是否热休克蛋白70的表达/功能的损失是必要的，足够的发展自发性和致癌物质诱导的结肠癌的小鼠慢性结肠炎。将采用体外和体内方法的组合，后者包括基因靶向的Hsp 70缺失和上皮细胞或骨髓细胞特异性Hsp 70转基因表达的新模型。通过这些研究获得的见解将提供原则证据，即损害肠道内稳态的过程可能有助于IBD和炎症相关结肠癌的发展。因此，恢复肠道内稳态的策略对于预防、治疗和改变炎症性肠病的自然史非常重要。 公共卫生相关性本提案将检验以下假设：诱导型热休克蛋白Hsp 70对维持肠道内稳态至关重要，其在发炎粘膜中的表达不足有助于慢性结肠炎和结肠炎相关结肠癌的发展。恢复炎症黏膜中Hsp 70表达的策略对于预防、治疗和改变炎症性肠病的自然史将是重要的。