BIOENGINEERING AN ARTIFICIAL BETA CELL

描述（直接从应用程序中获取）：此目标 该项目的目的是生产一种替代β细胞的来源， 治疗胰岛素依赖型糖尿病（IDDM）。我们 最近将胰岛素表达靶向于中叶（IL） 转基因非肥胖糖尿病（NOD）小鼠的垂体， 人胰岛素依赖型糖尿病。这些小鼠的垂体组织分泌大量IL 通过受调节的分泌途径分泌大量胰岛素，类似于胰岛 β细胞然而，与产生胰岛素的胰岛β细胞相比， 细胞，产生胰岛素的IL垂体没有受到细胞的攻击。 免疫系统.值得注意的是，移植少量的 转基因IL组织进入糖尿病NOD小鼠导致恢复 糖尿病症状的完全逆转。的 垂体中叶细胞缺乏自身免疫， 分泌真正的胰岛素提高了这些细胞类型的潜力， 胰岛素依赖型糖尿病的治疗。 该项目的主要目标是现在引入 分泌胰岛素的IL组织响应于 葡萄糖和其它生理促分泌素（例如，餐）。的 葡萄糖感知的要求最初将使用 重组腺病毒基因递送系统。其次，最优 这些成分将在胰岛素分泌IL组织中稳定表达， 使用转基因小鼠技术的NOD小鼠。我们将评估这些 生物工程组织，当移植到糖尿病NOD小鼠，可以导致 葡萄糖稳态的长期正常化，以及他们是否可以 仍然可以避免针对β细胞的自身免疫破坏过程 胰岛素依赖型糖尿病我们将与项目4合作评估 与项目1和3中衍生的胰岛相比， 在异种移植中存活下来从另一方获得的信息 根据需要，将使用项目来进一步修改这些生物工程IL 细胞以提高移植物存活率。这些策略可能会创造一部小说 用于糖尿病治疗的“人造β细胞”的来源。

Description (taken directly from the application): The goal of this project is to produce a source of surrogate beta cells that will be suitable for the treatment of insulin dependent diabetes mellitus (IDDM). We have recently targeted insulin expression to the intermediate lobe (IL) of the pituitary of transgenic nonobese diabetic (NOD) mice, a model for human IDDM. The IL pituitary tissues from these mice secreted abundant amounts of insulin via a regulated secretory pathway, similar to islet beta cells. However, in contrast to the insulin-producing islet beta cells, the insulin-producing IL pituitaries were not attacked by cells of the immune system. Remarkably, transplantation of small amounts of the transgenic IL tissues into diabetic NOD mice resulted in the restoration of near-normoglycemia and the complete reversal of diabetic symptoms. The absence of autoimmunity in intermediate lobe pituitary cells engineered to secrete bone fide insulin has raised the potential of these cell types for the treatment of IDDM. The major objective of this project is to now introduce into the insulin-secreting IL tissues the ability to secrete insulin in response to glucose and other physiological secretagogues (e.g., meals). The requirements for glucose sensing will initially be tested utilizing a recombinant adenovirus gene delivery system. Subsequently, the optimal components will be stably expressed in the insulin-secreting IL tissues of NOD mice using transgenic mouse techniques. We will assess whether these bioengineered tissues, when transplanted into diabetic NOD mice, can lead to long term normalization of glucose homeostasis and whether they can still avoid the autoimmune destructive process targeted against beta cells in IDDM. We will evaluate, in collaboration with Project 4, the ability of these cells compared to the islets derived in Projects 1 and 3, to survive xenogeneic transplantation. The information gained from the other projects will be used, as needed, to further modify these bioengineered IL cells to enhance graft survival. These strategies may create a novel source of "artificial beta cells" for diabetes treatment.