Elucidating the Role of VEGF-A in Pancreatic Islet Innervation

阐明 VEGF-A 在胰岛神经支配中的作用

• 批准号: 7809361
• 负责人: Rachel Byerley Reinert
• 金额: $ 2.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809361
• 关键词: Abbreviations; Ablation; Address; Adult; Angiogenic Factor; Biological Assay; Blood Platelets; Blood Vessels; CD31 Antigens; Cell Adhesion Molecules; Cell physiology; Cells; Communication; Complex; Data; Defect; Dependence; Development; Diabetes Mellitus; Diphtheria Toxin; Embryo; Endocrine; Endocrine Glands; Endothelial Cells; Enteral; Functional disorder; Ganglia; Gene Targeting; Glial Fibrillary Acidic Protein; Gliosis; Glucose; Glucose tolerance test; Goals; Growth Factor; Homeobox; Hormones; Immunohistochemistry; In Vitro; Islet Cell; Islets of Langerhans; Lead; Measurement; Mediating; Migration Assay; Molecular; Morphology; Mus; Myxoid cyst; Nerve; Nerve Fibers; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Perfusion; Physiological; Process; Production; Proteins; Proteolipids; Recruitment Activity; Role; Schwann Cells; Signal Transduction; Stimulus; Structure; Therapeutic; TimeLine; Toxin; Tubulin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vascularization; Weaning; afferent nerve; cell motility; cell type; diphtheria toxin receptor; endocrine pancreas development; factor A; improved; in vivo; insulin secretion; islet; nerve supply; postnatal; receptor; relating to nervous system; research study; response

DESCRIPTION (provided by applicant): The pathophysiology of type 2 diabetes involves inadequate insulin secretion from pancreatic ¿-cells in the islet of Langerhans. Islet endocrine cells secrete hormones in response to physiologic stimuli such as glucose, metabolites, other hormones, and neural signals. This coordinated response depends on communication between endocrine, endothelial, and neural cells within the islet. The goal of these studies is to provide a better understanding of the factors that mediate the co-development of islet cells to form a functional endocrine organ. Cre-lox-mediated inactivation of pancreatic vascular endothelial growth factor A (VEGF-A) leads to reduced islet vascularization and impaired insulin secretion. Unexpectedly, reduced VEGF-A also impairs islet innervation. The first aim of this proposal is to examine the development of pancreatic islet innervation and elucidate the mechanism by which VEGF-A directs this process. First, the development of islet vascular and neural structures during the embryonic and postnatal periods will be followed in mice with pancreatic VEGF-A inactivation and in their wild-type counterparts. Next, in vitro cell migration assays will be used to reveal whether islet cell-derived VEGF-A or intra-islet endothelial cells mediate the recruitment of neural cells. These experiments will help determine the co-dependence of islet cells during islet formation. The second aim of this proposal will focus on the role of peri-islet Schwann cells, which undergo reactive gliosis in response to inactivation of pancreatic VEGF-A. Peri-islet Schwann cells will be ablated in mice using cell-specific expression of a toxin receptor, and the effects on islet cell organization, innervation, and function will be assessed. These studies will elucidate the role of peri-islet Schwann cells, whose role in islet function is currently unknown. RELEVANCE One central defect in type 2 diabetes is inadequate insulin secretion from pancreatic ¿-cells, so understanding ¿-cell function and dysfunction is of critical importance. These studies will determine how ¿ cells, blood vessels, and nerves in the pancreatic islet signal to each other, both during development and in the adult, and elucidate how these relationships are necessary for proper insulin secretion. A better understanding of islet development and function and could lead to improved therapeutic approaches for diabetes.

描述（由申请人提供）： 2型糖尿病的病理生理学涉及胰腺细胞胰岛素分泌不足， 朗格汉斯岛胰岛内分泌细胞响应生理刺激如葡萄糖、代谢物、其他激素和神经信号而分泌激素。这种协调一致的反应取决于 胰岛内的内分泌细胞、内皮细胞和神经细胞之间的通讯。这些研究的目的是更好地了解介导胰岛细胞共同发育形成功能性内分泌器官的因素。 Cre-lox介导的胰腺血管内皮生长因子A（VEGF-A）失活导致 胰岛血管形成减少和胰岛素分泌受损。出乎意料的是，减少的VEGF-A也损害胰岛神经支配。该建议的第一个目的是检查胰岛神经支配的发展，并阐明VEGF-A指导这一过程的机制。首先，在胚胎和出生后期间，胰岛血管和神经结构的发展将在胰腺VEGF-A失活的小鼠和野生型小鼠中进行。接下来，将使用体外细胞迁移测定来揭示胰岛细胞来源的VEGF-A或胰岛内内皮细胞是否介导神经细胞的募集。这些实验将有助于确定在胰岛形成过程中胰岛细胞的相互依赖性。 该建议的第二个目的将集中在胰岛周许旺细胞的作用，其经历反应性神经胶质增生，以响应胰腺VEGF-A的失活。将使用毒素受体的细胞特异性表达消融小鼠中的胰岛周施旺细胞，并评估对胰岛细胞组织、神经支配和功能的影响。这些研究将阐明胰岛周围许旺细胞的作用，其在胰岛功能中的作用目前尚不清楚。 相关性 2型糖尿病的一个核心缺陷是胰腺细胞分泌胰岛素不足， 了解细胞功能和功能障碍是至关重要的。这些研究将确定胰岛中的细胞、血管和神经在发育过程中和成年后如何相互传递信号，并阐明这些关系对适当的胰岛素分泌是必要的。更好地了解胰岛发育和功能，可能会导致糖尿病治疗方法的改进。