NF-kB in the intestinal radiation response

NF-kB 在肠道辐射反应中的作用

• 批准号: 6951961
• 负责人: LAURENCE J EGAN
• 金额: $ 7.38万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6951961
• 关键词: DNA damage; apoptosis; cell type; fluorescence microscopy; gastrointestinal epithelium; immunocytochemistry; intestinal villi; ionizing radiation; laboratory mouse; nuclear factor kappa beta; protein structure function; radiation therapy; radiation therapy dosage; small intestines; stem cells; therapy adverse effect

DESCRIPTION (provided by applicant): Injury to the small intestinal epithelium is a major adverse effect of abdominal radiation therapy. Ionizing radiation (IR) induces apoptosis of epithelial cells in the crypts of the small intestine. Above a critical threshold of exposure, IR kills clonogenic stem cells leading to crypt death. This results in widespread mucosal injury and causes the acute post-IR gastrointestinal (GI) syndrome, which leads to malnourishment, sepsis and death. The long-term goal of this project is to characterize the molecular regulation of IR-induced intestinal injury. Our studies to date have revealed a previously unrecognized endogenous mechanism of protection against IR-induced apoptosis in intestinal epithelial cells: activation of the DNA damage- responsive transcription factor NF-kappa B. In the proposed research, we will determine the role of intestinal epithelial cell NF-kappa B in protection against the post-IR GI syndrome. Our central hypothesis is that intestinal epithelial cell NF-kappa B decreases the severity of the post-IR GI syndrome by inhibiting crypt death. In specific aim 1, determine the amount of IR required for NF-kappa B activation in the small intestine, the cell types that activate it and whether it is activated during crypt regeneration. In specific aim 2, we will determine if NF-kappa B affects the death or proliferative potential of crypt clonogenic stem cells, thereby affecting the development of post-IR GI syndrome. These results will provide mechanistic insight into an important medically relevant problem, amd will point the way towards novel therapies to prevent radiation injury to the intestines.

描述（由申请人提供）： 小肠上皮的损伤是腹部辐射疗法的主要不良影响。电离辐射（IR）诱导小肠隐窝中上皮细胞的凋亡。 IR在暴露的临界阈值之上，杀死导致隐窝死亡的克隆原生成细胞。这会导致广泛的粘膜损伤，并导致急性IR后胃肠道（GI）综合征，导致营养不良，败血症和死亡。该项目的长期目标是表征IR诱导的肠损伤的分子调节。迄今为止，我们的研究揭示了先前未识别的内源性内源性的防御IR诱导的肠上皮细胞凋亡的机制：DNA损伤反应转录因子NF-KAPPA B的激活B.在拟议的研究中，我们将确定肠道上皮细胞上皮细胞NF-KAPPA B在保护后IR GI GI GI综合征中的作用。我们的中心假设是，肠上皮细胞NF-kappa B通过抑制隐窝死亡来降低IR后GI综合征的严重程度。在特定目标1中，确定小肠中NF-kappa B激活所需的IR量，激活它的细胞类型以及是否在隐窝再生过程中激活它。在特定的目标2中，我们将确定NF-kappa B是否影响隐窝克隆干细胞的死亡或增殖潜力，从而影响IR后IR GI综合征的发展。这些结果将提供对重要的医学相关问题的机械洞察力，AMD将指向防止肠道辐射损伤的新疗法的道路。