Beta Cell Regeneration in Adult Pancreatic Islets

描述(申请人提供)：产生胰岛素的β细胞被破坏导致IDDM。我们目前的工作目标是确定成人胰岛是否含有β前体细胞，并在以后建立促进β细胞新生的方案。我们开发了一种新的系统，在该系统中，新的β细胞(NBC)被诱导从假定的β细胞前体分化出来。在用一种特殊的β细胞毒素链脲佐菌素(SZ)耗尽现有的β细胞后，我们发现表达胚胎β细胞表型特征的细胞在胰岛分化，这一步骤紧随其后的是NBC的出现。此外，通过胰岛素治疗恢复正常血糖显著增加了β细胞的新生。我们现在建议确定NBC的来源。在特定的目标#1中，我们将测试在正常血糖恢复后在SZ治疗的小鼠的胰岛中重新出现的IN+细胞是NBC的细胞还是在毒素作用下存活的“老”β细胞。为了做到这一点，我们将测试在小鼠中是否发生了新的贝塔细胞，在这些小鼠中，通过分子标记的存在来识别“老的”贝塔细胞。在第二个具体目标中，我们将寻求确定NBC是否由胰腺的非β细胞产生。为了实现这一目标，我们将研究SZ和胰岛素治疗后正常血糖小鼠的β细胞新生过程，在这些小鼠中，胰升糖素和淀粉酶细胞及其产生的细胞被永久标记。这些方法可以证明胰岛内前体细胞在这个和其他IDDM模型中在体内的β细胞再生中发挥重要作用的假设。

DESCRIPTION (provided by applicant): Destruction of the insulin-producing beta cells leads to IDDM. The present goal of our work is to ascertain whether islets of adults contain beta precursor cells and to later establish protocols that will promote beta cell neogenesis. We developed a novel system in which new beta cells (NBC's) are induced to differentiate from putative beta cell precursors. Following depletion of existing beta cells by streptozotocin (SZ), a specific beta cell toxin, we found that cells expressing the phenotype characteristic of embryonic beta cells differentiated in islets and that this step was followed by the appearance of NBC's. Moreover, the restoration of normoglycemia by insulin therapy dramatically increased beta cell neogenesis. We now propose to identify the source of the NBC's. In specific aim #1, we will test whether IN+ cells that reappear in islets of SZ-treated mice following restoration of normoglycemia are NBC's or "old" beta cells that survived the effect of the toxin. To do this, we will test whether beta cell neogenesis occurs in mice in which "old" beta cells are identified by the presence of a molecular marker. In the specific aim #2, we will seek to determine whether the NBC's are generated by non-beta cells of the pancreas. To accomplish this goal, we will examine the process of beta cell neogenesis following SZ and insulin treatment in normoglycemic mice in which glucagon and amylase cells and the cells they generate are permanently labeled. These approaches could lend proof to the hypothesis that intra-islet precursors play an important role in beta cell regeneration in vivo in this and other models of IDDM.