ENTEROCYTE APOPTOSIS AFTER INTESTINAL RESECTION

肠切除后肠细胞凋亡

• 批准号: 8207552
• 负责人: BRAD Wayne WARNER
• 金额: $ 3.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207552
• 关键词: Apoptosis; Area; Attenuated; Back; Binding Sites; Cell Culture Techniques; Cell Death; Cessation of life; Clinical; Cyclic AMP-Dependent Protein Kinases; Data; Enterocytes; Epidermal Growth Factor Receptor; Excision; Family member; Funding; Generations; Genes; Goals; Grant; Health; Homeostasis; Induction of Apoptosis; Innovative Therapy; Intestinal Mucosa; Intestines; Knockout Mice; Laboratories; Lead; MAPK14 gene; Measures; Mitogen-Activated Protein Kinase 14; Mitogen-Activated Protein Kinases; Molecular; Mus; Patients; Process; Promoter Regions; Rage; Receptor Inhibition; Receptor Signaling; Regulation; Role; STAT1 protein; Short Bowel Syndrome; Signal Pathway; Small Intestines; Surface; Testing; Transcription Coactivator; Translations; Veins; Villus; base; bench to bedside; design; effective therapy; ileum; improved; in vitro Model; in vivo; innovation; new therapeutic target; nutrition; prevent; programs; promoter; research study; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Intestinal adaptation is a critical, compensatory response to massive small bowel resection (SBR) and characterized by increased enterocyte turnover as gauged by elevated rages of both proliferation and apoptosis. The significance of apoptosis to the magnitude of adaptation was revealed during the previous funding cycle of this grant as amplified adaptation was observed when apoptosis was actively inhibited. While the mechanisms(s) for elevated apoptosis after SBR is presently unknown, we have established that this response is regulated by epidermal growth factor receptor (EGFR) signaling and requires expression of the proapototic Bcl02 family member Bax and the transcription factor signal transducer and activator of transcription (STAT)-1. As an extension of these key observations, we propose the global hypothesis that EGFR signaling modulates the expression and activity of Bax to regulate resection-induced apoptosis. To test this hypothesis our aims are: 1) Determine the role for STAT-1 in the regulation of Bax expression during intestinal adaptation. STAT-1 expression and activity will be determined in the ileum after SBR as well as in cell culture following induction of apoptosis. The effect of STAT-1 deficiency on Bax expression and apoptosis will be measured and putative STAT-1 binding sites on Bax promoter will be investigated. 2) Determine the role of p38alpha mitogen-activated protein kinase (MAPK) as modulator of Bax activity during resection induced adaptation. A temporal and spatial profile of p38 expression/activity and Bax activation will be recorded after SBR in mice and complementary in vitro models of apoptosis. The effect of conditional, intestine-specific deletion of p38 expression on Bax activity and apoptosis will be determined after SBR. 3) Determine the mechanism for EGFR regulation of Bax expression and activity. The effect of enhanced or disrupted EGFR signaling on STAT-1 and p38 activation and expression will be recorded. The effect of attenuated STAT-1 or p38 expression in the context of EGFR inhibition on apoptosis and Bax activity and expression will be determined. The proposed studies in this application will identify the most relevant signaling pathway to direct apoptosis after massive SBR. A thorough understanding of the precise mechanism for induction of apoptosis is fundamental for bench-to-bedside translation of therapeutic targets intended to maximally stimulate regrowth of the intestinal mucosa in response to massive intestinal loss. PUBLIC HEALTH RELEVANCE: Following massive intestinal loss, the remaining bowel attempts to grow back to compensate. If this response is incomplete, the patient will be subjected to a lifetime of nutrition by vein and all the associated complications. This project is designed to understand the contribution of mucosal cell death to the process of intestinal regrowth. Understanding the exact molecular regulation of this important response may lead to innovative therapy intended to improve intestinal regrowth following a catastrophic loss of the intestine.

描述（由申请人提供）：肠道适应性是对大肠小肠切除（SBR）的关键，补偿性反应，其特征是肠肠细胞周转率增加，因为增殖和凋亡的愤怒升高。在该赠款的先前资助周期中，凋亡对适应大小的重要性是在主动抑制凋亡时观察到的放大适应性的。尽管目前未知SBR后凋亡升高的机制，但我们已经确定该反应受表皮生长因子受体（EGFR）信号传导的调节，并且需要表达息肉性BCL02家族成员BAX和转录因子信号信号信号转录器和转录的激活因子（Stat）-1 -1 -1。作为这些主要观察结果的扩展，我们提出了一个全球假设，即EGFR信号传导调节BAX调节切除诱导的细胞凋亡的表达和活性。为了检验这一假设，我们的目的是：1）确定STAT-1在肠道适应过程中BAX表达中的作用。 STAR-1表达和活性将在SBR之后在回肠以及诱导凋亡后的细胞培养中确定。将测量Stat-1缺乏对BAX表达和凋亡的影响，并研究假定的STAT-1结合位点对BAX启动子的影响。 2）确定p38Alpha有丝分裂原激活的蛋白激酶（MAPK）作为切除诱导的适应过程中BAX活性的调节剂的作用。在小鼠和互补的凋亡模型中，将记录p38表达/活性和BAX激活的时间和空间谱。 SBR后，将确定p38表达的条件特异性缺失对BAX活性和凋亡的影响。 3）确定EGFR调节BAX表达和活性的机制。将记录增强或破坏的EGFR信号对Stat-1和p38激活和表达的影响。在EGFR抑制作用对凋亡和BAX活性和表达的背景下，衰减的STAT-1或P38表达的影响将得到确定。在本应用中提出的研究将确定大规模SBR后直接凋亡的最相关信号传导途径。对诱导凋亡的确切机制的透彻理解对于旨在最大程度地刺激肠道粘膜再生的治疗靶标的基准转换是基础。公共卫生相关性：在巨大的肠道损失之后，其余的肠子试图恢复赔偿。如果这种反应不完整，则患者将因静脉和所有相关并发症而经历一生的营养。该项目旨在了解粘膜细胞死亡对肠道再生过程的贡献。了解这种重要反应的确切分子调节可能会导致旨在改善肠道灾难性丧失后肠道再生的创新疗法。

项目成果

Preventing enterocyte apoptosis after massive small bowel resection does not enhance adaptation of the intestinal mucosa.

大规模小肠切除术后防止肠上皮细胞凋亡并不能增强肠粘膜的适应。

• DOI: 10.1016/j.jpedsurg.2004.02.007
• 发表时间: 2004
• 期刊: Journal of pediatric surgery
• 影响因子: 2.4
• 作者: Juno,RussellJ;Knott,AndrewW;Profitt,SherriA;Jarboe,MarcusD;Zhang,Yufang;Erwin,ChristopherR;Warner,BradW
• 通讯作者: Warner,BradW