Cytoprotective Role of Heat Shock Proteins in IBD

肠道动态平衡是维持正常状态的要素的基本动态平衡 粘膜功能、完整性、自我更新和宿主防御。在急性疾病中，病原性的侮辱是自我 有限的肠道内环境平衡得以恢复。在炎症性肠病(IBD)中，肠 由于慢性、破坏性的粘膜炎症持续存在，体内平衡无法恢复。 然而，考虑得较少的是，恢复 在令人不快的侮辱得到解决的过程中，甚至在解决之后，肠道内环境的稳定也会受到损害。这项建议 因此，我将检验一种假设，即可诱导的热休克蛋白Hsp70对 维持肠道内环境稳定及其在炎症过程中的表达不足有助于 慢性结肠炎和结肠炎相关性结肠癌的发展。对这一概念的支持来自 观察结果：(1)热休克蛋白70具有强大的细胞保护和抗炎作用；(2) 在实验性结肠炎和人类结肠炎中观察到HSP70的表达下调，导致粘膜 更容易受到伤害，并加剧炎症反应，(3)基因靶向缺失Hsp70 将DSS诱导的自限性结肠炎转变为慢性IBD样结肠炎，以及(4)之后 AOM/DSS挑战，多灶性扁平异型增生到癌症序列的结肠癌在Hsp70- 基因缺陷的小鼠，而不是它们的野生型小鼠，它们会发展成从息肉到癌症的零星序列 结肠癌，以及Hsp70的强阳性表达与散发性人类结肠癌有关，但与此无关 IBD癌症。 提出了三个特定的目标来研究Hsp70(在上皮和免疫来源中的作用 细胞)在肠道内稳态，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HSP70是否是必需的 维持肠道内环境平衡及其在急性炎性反应中的表达下调 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。第二， 导致HSP70选择性翻译下调的机制(S) 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/功能的丧失是自发性和自发性高血压发生的必要条件和充分条件。 慢性结肠炎小鼠致癌物诱导的结肠癌。体外和体内的结合 将采用的方法，后者包括新的模型的基因靶向-Hsp70缺失和 上皮细胞或髓系细胞特异性的Hsp70转基因表达。通过这些研究获得的见解 将提供破坏肠道内稳态的过程可能有助于 炎症性肠病和炎症相关结肠癌的发展。恢复肠道功能的策略 因此，动态平衡对于预防、治疗和改变红斑狼疮的自然历史非常重要。 炎症性肠病。这项提议将检验一种假设，即可诱导的热休克蛋白， HSP70是维持肠道内环境稳定所必需的，但它的缺陷 炎症黏膜中的表达有助于慢性结肠炎的发生和发展 结肠炎相关性结肠癌。恢复炎症组织中Hsp70表达的策略 粘膜对于预防、治疗和改变红斑狼疮的自然历史具有重要意义。 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.