ANGIOGENESIS IN INTESTINAL ADAPTATION

肠道适应中的血管生成

• 批准号: 9248350
• 负责人: BRAD Wayne WARNER
• 金额: $ 34.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248350
• 关键词: Area; Blood Vessels; CXC Chemokines; Caring; Cessation of life; Child; Coagulation Process; Development; Digestion; Enterocytes; Epidermal Growth Factor Receptor; Epithelial; Excision; Fatty acid glycerol esters; Goals; Growth; Hypoxia; Hypoxia Inducible Factor; Impairment; In Vitro; Infection; Intestines; Intravenous; Knockout Mice; Laboratories; Length; Ligands; Liver Failure; Metabolic; Microscopy; Morbidity - disease rate; Operative Surgical Procedures; Oxygen; Patient-Focused Outcomes; Patients; Process; Receptor Signaling; Savings; Short Bowel Syndrome; Signal Transduction; Small Intestines; Surface; Survival Rate; Technology; Testing; Time; Transcription Coactivator; Weaning; Weight Gain; absorption; angiogenesis; chemokine; cost; effective therapy; functional adaptation; in vivo; innovation; intestinal villi; mortality; novel therapeutic intervention; nutrient absorption; nutrition; overexpression; public health relevance; receptor expression; response

 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.

 描述（由适用提供）：短肠综合征（SBS）是由于小肠道长度的手术损失而导致的。为了应对这一损失，其余的肠子中发生了适应反应，其特征是肠肠细胞增殖增加，导致绒毛较高，隐窝更深和粘膜表面积扩大。 SBS患者揭示了适应性的意义，这些患者最终能够随着时间的流逝而完全从静脉内（IV）营养中完全断奶。如果不足，对IV营养的需求及其相关的发病率是永久的。除了增强的肠上皮增殖外，我们还揭示了适应性与肠内的新血管生长（血管生成）有关。此外，我们发现SBR与氧递送和缺氧诱导因子-Alpha（HIF1A）的水平升高有关。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。尚不清楚切除相关血管生成的显着性和机制。该项目旨在检验正常肠道适应需要血管生成的总体假设。血管生成在SBR诱导的肠道适应性中的重要性将在以下目的中进行检查：AIM 1将通过首先表征SBR和低氧对上皮和内皮HIF-1A和EGFR表达的影响，确定响应SBR诱导的肠道肠道缺氧的机制，以及EGFR的表达。接下来，我们将阐明上皮或内皮EGFR信号受损对SBR后O2递送，HIF1A表达和肠血管生成的影响。最后，我们将确定上皮受损或 SBR后O2递送和肠血管生成上的内皮HIF1A表达。在AIM 2中，我们将通过确定肠内内皮或上皮EGFR或HIF1A对CXCL5在体外和体内CXCL5表达的影响，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因子。在AIM 3中，我们将通过阐明扰动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。我们还将定义HIF1A，EGFR和CXCL5对腺病毒指导的内皮过表达对切除相关的血管生成和适应反应的影响。因此，表征适应的精确机制以及如何加速该过程对于我们的长期目标至关重要，即为遭受大量肠道损失的患者开发更有效的治疗。