Elucidating the Role of VEGF-A in Pancreatic Islet Innervation

描述(由申请人提供)： 2型糖尿病的病理生理与胰腺细胞分泌胰岛素不足有关。 朗格汉斯岛。胰岛内分泌细胞在生理刺激下分泌激素，如葡萄糖、代谢物、其他激素和神经信号。这种协调一致的反应取决于 胰岛内内分泌细胞、内皮细胞和神经细胞之间的通讯。这些研究的目的是为了更好地了解调节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失活导致 胰岛血管化减少，胰岛素分泌受损。出乎意料的是，血管内皮生长因子-A的减少也会损害胰岛的神经支配。这一建议的第一个目的是研究胰岛神经的发育，并阐明血管内皮生长因子-A指导这一过程的机制。首先，在胰腺血管内皮生长因子-A失活的小鼠和野生型小鼠中，将跟踪胚胎和出生后胰岛血管和神经结构的发育。接下来，体外细胞迁移分析将被用来揭示胰岛细胞来源的血管内皮生长因子-A或胰岛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胰岛细胞在胰岛形成过程中的相互依赖性。 这项提议的第二个目的将集中在胰岛周围雪旺细胞的作用，这些细胞在胰腺血管内皮生长因子-A失活的情况下发生反应性胶质增生。小鼠的胰岛周围雪旺细胞将通过细胞特异性表达毒素受体来消融，并将评估其对胰岛细胞组织、神经支配和功能的影响。这些研究将阐明胰岛周围雪旺细胞的作用，其在胰岛功能中的作用目前尚不清楚。 相关性 2型糖尿病的一个中心缺陷是胰腺细胞分泌的胰岛素不足，因此 了解细胞的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时是如何相互传递信号的，并阐明这些关系对于正常的胰岛素分泌是如何必要的。更好地了解胰岛的发育和功能，可能会导致改进糖尿病的治疗方法。

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.