Pancreatic Intra-Islet Ducts

描述(由申请人提供)：更好地了解如何形成新的细胞，以及它们可能从哪里产生，对于我们为糖尿病患者设计细胞替代疗法的策略是至关重要的。细胞复制似乎是年轻健康动物产生新细胞的主要机制，也许在人类中也是如此。然而，非细胞来源的细胞新生也可能发挥重要作用，特别是在糖尿病患者和老年人中，这些人的细胞复制能力似乎有所减弱。我们认为，胰管已经成为最有可能成为新细胞来源的非细胞来源。100多年来，胰管和胰岛之间的解剖“联系”已经被很好地描述了，大多数胰岛显示出某种形式的接触，或者至少接近胰管。然而，在这里，在一个基因改变的小鼠模型中，胰腺部分切除后细胞不增殖，我们描述了胰腺部分切除后从现有的大导管中相当戏剧性地长出新的导管结构。这些萌发的导管长入胰岛并在其中分枝。初步实验强烈表明，这些胰岛内的导管细胞可以转化为胰岛细胞。有趣的是，如果将这些相同的小鼠饲养到胰腺切除后胰岛细胞恢复增殖的背景中，这种导管生长在很大程度上受到抑制。此外，我们发现侵入胰岛的导管通常在幼鼠和年轻人类中短暂存在，首先出现在大约两周大的小鼠身上，但在八周大后几乎完全消失。在那里，我们再次(至少在老鼠身上)发现，幼鼠体内的这些导管细胞会产生新的胰岛素+细胞。在这项建议中，我们首先将努力描述这些胰岛内导管结构产生的过程，特别是在它们产生的常规导管网络中是否存在特定的亚群。其次，我们将研究导致它们形成的分子途径，并更好地定义这些侵袭性导管细胞的表型。这项分析的一部分将考虑这些导管结构起源于胰腺导管腺的可能性。第三，我们将研究从这些胰岛内导管特异性形成的胰岛素+细胞，并不仅确定它们的确切表型，而且 还要寻找它们是如何从导管细胞产生的线索。我们认为，更好地了解这些胰岛内导管结构及其产生的胰岛素+细胞将对我们未来在体外和体内产生新细胞的能力具有重要意义。

DESCRIPTION (provided by applicant): A better understanding of how to form new ¿-cells, and from where they might arise is of the utmost importance toward our goal of devising a strategy for ¿-cell replacement therapy for diabetics. ¿-cell replication appears to be the predominant mechanism underlying the generation of new ¿-cells in young healthy animals, and perhaps in humans. However, neogenesis of ¿-cells from non-¿-cell sources may also play an important role, particularly in diabetics and in the elderly, where the capacity for ¿-cell replicaion appears to be diminished. We feel that the pancreatic ducts have emerged as the most likely candidate for a non-¿-cell source of new ¿-cells. An anatomical "association" between the pancreatic ducts and the islets has been well-described for over 100 years, with most islets displaying some sort of contact with, or at least proximity to ducts. Here, however, in a genetically altered mouse model in which ¿-cells do not proliferate after partial pancreatectomy, we describe a fairly dramatic sprouting of new ductal structures from existing large ducts after partial pancreatectomy. These sprouting ducts grow into and ramify within islets. Preliminary experiments strongly suggest that these intra-islet duct cells convert into islet cells. Interestinly, this ductal growth is largely suppressed if these same mice are bred into a background where proliferation of the islet cells after a pancreatectomy is restored. In addition, we found that suc islet-invading ducts are normally present transiently in young mice and in young humans, first appearing in mice at around two weeks of age, but then almost completely absent after eight weeks of age. There again (at least in mice) we found that those ductal cells in the young mice give rise to new insulin+ cells. In this proposal we will first strive to characterize the process y which these intra-islet duct structures arise, and in particular whether there is a specific subpopulation within the regular ductal network from which they arise. Second, we will study the molecular pathways that lead to their formation, and better define the phenotype of these invading ductal cells. Part of this analysis will entertain the possibility that these ductal structures arise from pancreatic ductal glands. Third, we will study the insulin+ cells that specifically form from these intra-islet ducts, and determine not only their precise phenotype, but also search for clues as to how they arose from the duct cells. We feel that a better understanding of these intra-islet ductal structures and the insulin+ cells they give rise to will have important implications for our ability to generate new ¿-cells in the future, both in vitro an in vivo.