ANGIOGENESIS IN INTESTINAL ADAPTATION

 描述（由申请人提供）：短肠综合征（SBS）是由于手术导致小肠长度显著减少。作为对这种损失的响应，在剩余的肠中发生适应性反应，其特征在于肠上皮细胞增殖增加，导致绒毛更高、隐窝更深和粘膜表面积扩大。SBS患者最终能够随着时间的推移完全脱离静脉（IV）营养，适应的重要性也随之显现。如果不充分，则需要静脉营养及其相关的发病率是永久性的。除了增强肠上皮细胞增殖，我们已经发现，适应与新的血管生长（血管生成）在肠道内。此外，我们发现SBR与氧输送减少和缺氧诱导因子-α（HIF 1a）水平升高有关。最后，切除诱导的血管生成与促血管生成趋化因子（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目前尚不清楚。该项目旨在测试血管生成是正常肠道适应所需的总体假设。血管生成在SBR诱导的肠适应中的意义将在以下目的中进行检查：目的1将通过首先表征SBR和缺氧对上皮和内皮HIF-1 α和EGFR表达以及EGFR活性的影响来确定血管生成响应SBR诱导的肠缺氧的机制。接下来，我们将阐明受损的上皮或内皮EGFR信号传导对SBR后O2输送、HIF 1a表达和肠血管生成的影响。最后，我们将确定受损的上皮细胞或 SBR后O2输送和肠道血管生成中的内皮HIF1a表达。在目标2中，我们将通过测定破坏的肠内皮或上皮EGFR或HIF 1a对体外和体内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HIF 1a是否是CXCL 5表达的直接转录激活因子。在目标3中，我们将通过阐明干扰血管生成的代谢后果来确定CXCL5表达和血管生成对功能适应的贡献。我们还将确定腺病毒介导的HIF 1a、EGFR和CXCL 5的内皮过表达对切除相关血管生成和适应反应的影响。因此，描述适应的精确机制以及如何加速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.