Pancreatic Intra-Islet Ducts

描述（由申请人提供）：更好地了解如何形成新细胞，以及它们可能从哪里产生，对于我们设计糖尿病患者细胞替代治疗策略的目标至关重要。细胞复制似乎是年轻健康动物中新细胞产生的主要机制，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，他们的细胞复制能力似乎减弱了。我们认为胰管已经成为最有可能成为新细胞的非细胞来源的候选者。胰管和胰岛之间的解剖学“关联”已经被很好地描述了100多年，大多数胰岛都与胰管有某种接触，或者至少靠近胰管。然而，在基因改变的小鼠模型中，细胞在部分胰腺切除术后不增殖，我们描述了部分胰腺切除术后现有大导管中相当戏剧性的新导管结构的发芽。这些芽管在胰岛中生长并分叉。初步实验有力地表明，这些胰岛内管细胞转化为胰岛细胞。有趣的是，如果将这些小鼠饲养在胰腺切除术后胰岛细胞增殖恢复的环境中，这种导管的生长在很大程度上受到抑制。此外，我们发现这种入侵胰岛的导管在幼鼠和人类中通常是短暂存在的，在幼鼠大约两周龄时首次出现，但在八周龄后几乎完全消失。我们再次（至少在老鼠身上）发现年轻老鼠的导管细胞产生了新的胰岛素+细胞。在本提案中，我们将首先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规则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，并更好地定义这些入侵导管细胞的表型。部分分析将考虑这些导管结构来自胰管腺的可能性。第三，我们将研究这些胰岛内导管特异性形成的胰岛素+细胞，不仅要确定它们的精确表型，还要确定它们的特异性

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.