ANGIOGENESIS IN INTESTINAL ADAPTATION

 描述(由申请人提供)：短肠综合征(SBS)是由外科手术造成的大量小肠长度的丧失引起的。作为对这种缺失的反应，剩余的肠道发生了适应性反应，其特征是肠细胞增殖增加，导致绒毛更高，隐窝更深，粘膜表面积扩大。适应的重要性在SBS患者中显现出来，他们最终能够随着时间的推移完全摆脱静脉(IV)营养。如果不足，对静脉营养的需求及其相关发病率是永久性的。除了促进肠细胞增殖，我们还发现适应与肠道内新血管的生长(血管生成)有关。此外，我们还发现SBR与氧输送减少和低氧诱导因子-α(HIF1a)水平升高有关。最后，切除诱导的血管生成与原血管生成趋化因子(C-X-C)配体5(CXCL5)的表达增加有关。切除相关血管生成的意义和机制(S)目前尚不清楚。这个项目试图验证一个重要的假设，即血管生成是正常肠道适应所必需的。血管生成在SBR诱导的肠适应中的意义将从以下几个方面进行研究：目的1首先研究SBR和低氧对肠上皮和内皮细胞HIF-1a和EGFR表达及EGFR活性的影响，以确定SBR诱导的肠低氧反应中血管生成的机制。接下来，我们将阐明受损的上皮或内皮细胞EGFR信号对SBR后O2输送、HIF1a表达和肠道血管生成的影响。最后，我们将确定受损的上皮细胞或 内皮细胞HIF1a在SBR后氧输送和肠道血管生成中的表达在目标2中，我们将通过体外和体内检测受损的肠内皮细胞或上皮细胞EGFR或HIF1a对CXCL5表达的影响来确定SBR后CXCL5表达增加的机制。我们还将确定HIF1a是否是CXCL5表达的直接转录激活剂。在目标3中，我们将通过阐明干扰的血管生成的代谢后果来确定CXCL5的表达和血管生成对功能适应的贡献。我们还将确定腺病毒引导的内皮细胞过表达HIF1a、EGFR和CXCL5对切除相关血管生成和适应反应的影响。因此，准确描述适应机制以及如何加快这一过程对于我们为遭受大量肠道损失的患者开发更有效的治疗方法的长期目标至关重要。

 DESCRIPTION (provided by applicant): Short bowel syndrome (SBS) results from the surgical loss of a significant of small intestinal length. In response to this loss, an adaptation response occurs in the remaining bowel characterized by increased enterocyte proliferation leading to taller villi, deeper crypts, and an expanded mucosal surface area. The significance of adaptation is revealed in SBS patients who ultimately are able to wean completely from intravenous (IV) nutrition over time. If insufficient, the need for IV nutrition and its allied morbidity is permanet. Besides enhanced enterocyte proliferation, we have revealed that adaptation is associated with new blood vessel growth (angiogenesis) within the intestine. Further, we have found that SBR is associated with diminished oxygen delivery and elevated levels of hypoxia-inducible factor-alpha (HIF1a). Finally, resection-induced angiogenesis is associated with increased expression of the proangiogenic chemokine (C-X-C) ligand 5 (CXCL5). The significance and mechanism(s) for resection-associated angiogenesis are presently unknown. This project seeks to test the overarching hypothesis that angiogenesis is required for normal intestinal adaptation. The significance of angiogenesis in SBR-induced intestinal adaptation will be examined in the following aims: Aim 1 will determine the mechanism for angiogenesis in response to SBR-induced intestinal hypoxia by first characterizing the effects of SBR and hypoxia on epithelial and endothelial HIF-1a and EGFR expression, and EGFR activity. Next, we will elucidate the effect of impaired epithelial or endothelial EGFR signaling on O2 delivery, HIF1a expression and intestinal angiogenesis after SBR. Finally, we will determine the effects of impaired epithelial or endothelial HIF1a expression on O2 delivery and intestinal angiogenesis after SBR. In Aim 2, we will determine the mechanism for increased CXCL5 expression following SBR by determining the effect of disrupted intestinal endothelial or epithelial EGFR or HIF1a on CXCL5 expression in vitro and in vivo. We will also determine whether HIF1a is a direct transcription activator of CXCL5 expression. In Aim 3, we will determine the contribution of CXCL5 expression and angiogenesis to functional adaptation by elucidating the metabolic consequences of perturbed angiogenesis. We will also define the effect of adenoviral-directed endothelial overexpression of HIF1a, EGFR, and CXCL5 on resection-associated angiogenesis and adaptation responses. Characterization of a precise mechanism for adaptation and how this process can be accelerated is therefore critical toward our long-term goal of developing more effective therapy for patients who have suffered massive intestinal loss.