Cytoprotective Role of Heat Shock Proteins in IBD

肠道内稳态是维持肠道正常运行的各种因素的基本的动态平衡 粘膜功能、完整性、自我更新和宿主防御。在急性疾病中，致病性损伤是自身的， 恢复了有限的肠道内稳态。在炎症性肠病（IBD）中，肠 由于慢性、破坏性粘膜炎症的持续，不能恢复体内平衡。 然而，较少考虑的是， 肠内稳态在损害性损伤期间甚至在损害性损伤消退之后受损。这项建议 因此，我将研究诱导型热休克蛋白Hsp 70对以下假设是必不可少的： 维持肠道内稳态，并且其在炎症期间的表达不足有助于 慢性结肠炎和结肠炎相关结肠癌的发展。对这一观点的支持来自 以下观察结果：（1）Hsp 70具有有效的细胞保护和抗炎特性，（2） 在实验性结肠炎和人类结肠炎中观察到Hsp 70表达下调， 更容易受到损伤和加剧炎症反应，（3）基因靶向缺失Hsp 70 将其他自限性DSS诱导的结肠炎转变为慢性IBD样结肠炎，以及（4） AOM/DSS激发，多灶性，扁平异型增生到癌症序列结肠癌在Hsp 70中发展- 缺陷型小鼠，而不是它们的野生型小鼠， 结肠癌，和5）稳健的Hsp 70表达与散发性人类结肠癌相关，但不 IBD癌症。 提出了三个具体的目标，以调查热休克蛋白70的作用（上皮与免疫源性 细胞）在肠道内稳态中的作用，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，我们将确定Hsp 70是否是必需的 维持肠道内稳态以及是否在急性炎症中下调表达 而在基于免疫的结肠炎模型中导致慢性或更严重的IBD样结肠炎。二是 导致观察到的Hsp 70选择性翻译下调的机制与 将定义肠道炎症和促炎细胞因子。最后，我们将研究是否 热休克蛋白70表达/功能的丧失对于自发性和 致癌物诱导的慢性结肠炎小鼠结肠癌。结合体外和体内 方法将被采用，后者包括基因靶向Hsp 70缺失的新模型， 上皮细胞或骨髓细胞特异性Hsp 70转基因表达。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。恢复肠道功能的策略 因此，体内平衡对于预防、治疗和改变疾病的自然史是重要的。 炎症性肠病。这项提议将检验诱导型热休克蛋白， Hsp 70是维持肠道内稳态所必需的， 在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在炎症中恢复Hsp 70表达的策略 粘膜对于预防、治疗和改变慢性阻塞性肺疾病的自然史将是重要的。 炎症性肠病。

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.