Mechanisms of pancreatic beta cell regeneration

描述(由申请人提供)： I型糖尿病的特征是胰腺分泌胰岛素的β细胞永久性丧失。我们的目标是了解决定胰腺β细胞质量的机制，作为开发糖尿病再生疗法的第一步。在与BCBC协调中心和该联盟成员的合作下，我们将使用转基因小鼠技术来检验β细胞具有显著再生能力的假设，该能力受特定信号的调节。具体目标是： 1.建立可调节的胰岛β细胞消融系统。我们的初步研究表明，小鼠可以从脉冲的β细胞消融中恢复过来。我们将详细描述消融和恢复的生理学和组织学方面的特征，以了解β细胞再生的机制。 2.确定再生β细胞的细胞来源。我们将使用遗传谱系追踪来确定干细胞和先前存在的贝塔细胞对贝塔细胞再生的贡献。 3.确定调节β细胞质量的信号特征。血液信号的相对重要性将被确定，重点是胰岛素和葡萄糖代谢的作用。此外，我们还将评估体内和体外β细胞去分化的意义。 来自这些研究的见解将被应用于原代β细胞培养，目的是提高产量，防止去分化和最大限度地减少细胞死亡。

DESCRIPTION (provided by applicant): Type I diabetes is characterized by the permanent loss of pancreatic insulin-producing beta cells. Our goal is to understand the mechanisms determining pancreatic beta cell mass, as a first step toward the development of regenerative therapies for diabetes. In collaboration with the BCBC Coordinating Center and members of the consortium, we will use transgenic mouse technology to examine the hypothesis that beta cells have a significant regenerative capacity, which is modulated by specific signals. The specific aims are to: 1. Develop a system for regulated ablation of pancreatic beta cells. Our preliminary studies indicate that mice can recover from a pulse of beta cell ablation. We will characterize in detail the physiological and histological aspects of ablation and recovery, in order to understand the mechanisims of beta cell regeneration. 2. Determine the cellular origins of regenerating beta cells. We will employ genetic lineage tracing to definitely determine the contributions of stem cells and pre-existing beta cells to beta cell regeneration. 3. Characterize the signals that regulate beta cell mass. The relative importance of blood-borne signals will be determined, with emphasis on the role of insulin and glucose metabolism. In addition, we will assess the significance of beta cell dedifferentiation in vivo and in vitro. Insights from these studies will be applied to primary beta cell cultures, with the aim of improving yield, preventing dedifferentiation and minimizing cell death