VEGF and Islet Vascularization

VEGF 和胰岛血管化

• 批准号: 8010999
• 负责人: ALVIN C POWERS
• 金额: $ 7.89万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010999
• 关键词: Affect; Angiogenic Factor; Architecture; Blood Glucose; Blood Vessels; Blood flow; Cells; Development; Endocrine; Endothelial Cells; Ephrins; Event; Gene Deletion; Gene Expression; Genes; Human; In Vitro; Inferior; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Ischemia; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Knowledge; Lead; Molecular; Pancreas; Physiology; Play; Production; Role; System; Testing; Therapeutic; Time; Tissues; Transplantation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vascular blood supply; Vascularization; angiogenesis; density; endocrine pancreas development; improved; in vivo; inhibitor/antagonist; insight; insulin secretion; islet; novel therapeutics; response; tumor; vasculogenesis

DESCRIPTION (provided by applicant): Pancreatic islets are extensively vascularized and this is important in their ability to sense the blood glucose and quickly secrete insulin. While islets receive up to 20 times more blood flow than surrounding pancreatic acinar tissue, the molecular factors and mechanisms responsible for islet vascularization are incompletely defined. New experimental evidence indicates that pancreatic islets express a number of angiogenic factors such as vascular endothelial growth factor (VEGF), angiopoietin (Ang), and ephrins, and that interactions between islet and endothelial cells are important in both islet development and vascularization. Pancreatic islet transplantation is an emerging therapy for type 1 diabetes, but major obstacles and gaps in our scientific knowledge preclude islet transplantation from being widely adapted. For example, islet isolation severs vascular connections that must be reestablished through angiogenesis/vasculogenesis; a large number of islets (perhaps the majority) die in the first days after transplantation while islet revascularization is occurring. VEGF is a crucial angiogenic factor in vascular development, angiogenesis in response to ischemia, and tumor-related angiogenesis. Even though pancreatic endocrine and exocrine cells share a common developmental lineage, islet cells have greater VEGF expression and vessel density than surrounding exocrine cells. To test the hypotheses that islet vascularization and revascularization requires production of VEGF-A by pancreatic islet cells, we will: 1) Elucidate the role of VEGF-A in pancreatic islet development and function using cell-specific, temporal inactivation of the VEGF-A gene using the Cre-loxP system. 2) Examine how gain or loss of VEGF-A function in pancreatic islets affects islet development and function. 3) Determine if gain or loss of VEGF-A function alters the revascularization, survival, or function of transplanted islets. These results should provide a better understanding of normal islet vascularization and how this affects normal islet development, architecture, and function. Information from the transplantation studies may suggest new therapeutic strategies to improve the rapidity and degree of revascularization of transplanted islets.

描述（由申请人提供）：胰岛广泛血管化，这对于它们感知血糖和快速分泌胰岛素的能力很重要。虽然胰岛比周围的胰腺腺泡组织接受多达20倍的血流量，但负责胰岛血管化的分子因素和机制尚未完全确定。新的实验证据表明，胰岛表达许多血管生成因子，如血管内皮生长因子（VEGF），血管生成素（Ang）和肝配蛋白，胰岛和内皮细胞之间的相互作用是重要的胰岛发育和血管化。胰岛移植是1型糖尿病的一种新兴疗法，但我们科学知识的主要障碍和差距阻碍了胰岛移植的广泛应用。例如，胰岛分离切断了必须通过血管生成/血管发生重建的血管连接;大量胰岛（可能是大多数）在移植后的第一天死亡，而胰岛血管重建正在发生。VEGF是血管发育、响应于缺血的血管生成和肿瘤相关的血管生成中的关键血管生成因子。尽管胰腺内分泌细胞和外分泌细胞具有共同的发育谱系，但胰岛细胞比周围的外分泌细胞具有更高的VEGF表达和血管密度。为了检验胰岛血管化和血管重建需要胰岛细胞产生VEGF-A的假设，我们将： 1)使用Cre-loxP系统，通过VEGF-A基因的细胞特异性暂时失活，阐明VEGF-A在胰岛发育和功能中的作用。2)检查胰岛中VEGF-A功能的获得或丧失如何影响胰岛发育和功能。3)确定VEGF-A功能的获得或丧失是否会改变移植胰岛的血运重建、存活或功能。这些结果应该提供一个更好的了解正常胰岛血管化，以及如何影响正常胰岛发育，结构和功能。来自移植研究的信息可能会提出新的治疗策略，以提高移植胰岛血管重建的速度和程度。