Role of fibrin-integrin interactions in supporting 2D and 3D pancreatic islet growth and function

1921年，班廷和贝斯特发现胰岛素，为现代糖尿病的治疗奠定了基础。然而，胰岛素治疗不能治愈糖尿病，也不能预防继发性并发症，而继发性并发症是导致这种疾病毁灭性发病率和死亡率的原因。通过胰岛移植替代产生胰岛素的细胞最有可能预防、逆转或稳定这些并发症。然而，胰岛的稀缺性和我们对影响胰岛生物学因素的知识的局限性是阻碍胰岛移植作为常规治疗的主要障碍。这一领域的进步需要对胰腺的发育生物学有透彻的了解。在目前的应用中，我们建议确定负责维持产生胰岛素的细胞的特定因素。我们的重点是整合素的作用，已知与细胞外基质蛋白相互作用的膜受体，控制胰腺器官发生和组织维持的几个方面。我们将对胰岛素生成细胞上的这些受体进行表征，研究它们与一种特定基质蛋白纤维蛋白的相互作用，并研究这些相互作用调节胰岛素生成细胞存活的机制。我们希望这些研究将促进适当的生物人工内分泌胰腺组织工程策略的发展。这种治疗将产生深远的经济效益和社会效益。

The discovery of insulin in 1921 by Banting and Best laid the foundation for the modern management of diabetes mellitus. However, insulin treatment cannot cure diabetes and will not prevent the secondary complications that are responsible for the devastating morbidity and mortality of this disease. Replacement of insulin-producing cells through islet transplantation has the best chance to prevent, reverse or stabilize these complications. However, the scarcity of islets and limitations in our knowledge of the factors influencing islet biology present a major obstacle precluding islet transplantation from being adopted as a routine treatment. Advancement in this field requires a thorough understanding of the developmental biology of the pancreas. In the present application we propose to identify specific factors that are responsible for the maintenance of insulin-producing cells. Our focus is on the role of integrins, membrane receptors that are known to interact with extracellular matrix proteins to control several aspects of pancreatic organogenesis and tissue maintenance. We will characterize these receptors on insulin-producing cells, examine their interactions with one specific matrix protein, fibrin, and study the mechanisms by which these interactions regulate survival of insulin-producing cells. It is our hope that these studies will facilitate the development of appropriate tissue engineering strategies for a bioartificial endocrine pancreas. This treatment will have far-reaching economic and social benefits.