Pancreatic Intra-Islet Ducts

胰岛内导管

• 批准号: 8626586
• 负责人: GEORGE K. GITTES
• 金额: $ 33.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626586
• 关键词: Acinar Cell; Adult; Age; Animals; Beta Cell; Breeding; Cell Lineage; Cell Proliferation; Cell Separation; Cells; Cues; Cultured Cells; Data; Diabetes Mellitus; Documentation; Duct (organ) structure; Ductal; Ductal Epithelial Cell; Elderly; Embryo; Endocrine; Epithelium; Fibrous capsule of kidney; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Generations; Gland; Goals; Growth; Hormones; Human; Implant; In Vitro; Infusion procedures; Insulin; Invaded; Islet Cell; Label; Lead; Molecular; Molecular Profiling; Mus; Nature; Pancreas; Pancreatectomy; Pancreatic duct; Pathway interactions; Phenotype; Play; Population; Process; Proliferating; Replacement Therapy; Role; Signal Transduction; Sorting - Cell Movement; Source; Structure; System; Techniques; Time; Transgenic Organisms; Tubular formation; Viral; comparative; diabetic; diabetic patient; in vivo; islet; mouse model; novel; older patient; progenitor; promoter; public health relevance; receptor; research study; response; transcriptome sequencing; transdifferentiation

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.

描述（由申请人提供）：更好地了解如何形成新的 β 细胞以及它们可能从何处产生，对于我们为糖尿病患者设计 β 细胞替代疗法的策略的目标至关重要。 ¿细胞复制似乎是年轻健康动物（也许还有人类）产生新的¡细胞的主要机制。然而，来自非β细胞来源的β细胞的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β细胞复制能力似乎有所减弱。我们认为胰管已成为最有可能的新 ¡ 细胞的非 ¡ 细胞来源的候选者。一百多年来，人们对胰管和胰岛之间的解剖学“关联”进行了很好的描述，大多数胰岛都与胰管有某种接触，或至少接近。然而，在这里，在基因改造的小鼠模型中，其中 β 细胞在部分胰腺切除术后不增殖，我们描述了在部分胰腺切除术后从现有的大导管中相当戏剧性地萌生出新的导管结构。这些发芽的导管生长进入胰岛并在胰岛内分支。初步实验强烈表明这些胰岛内导管细胞转化为胰岛细胞。有趣的是，如果将这些相同的小鼠饲养在胰腺切除术后胰岛细胞增殖恢复的背景中，这种导管生长会在很大程度上受到抑制。此外，我们发现胰岛入侵管通常在年轻小鼠和年轻人类中短暂存在，首先出现在两周龄左右的小鼠中，但在八周龄后几乎完全消失。我们再次发现（至少在小鼠中），年轻小鼠中的这些导管细胞会产生新的胰岛素+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，我们将研究导致其形成的分子途径，并更好地定义这些入侵导管细胞的表型。该分析的一部分将考虑这些导管结构源自胰腺导管腺的可能性。第三，我们将研究由这些胰岛内导管特异性形成的胰岛素+细胞，不仅确定其精确的表型，还确定其精确的表型。 还寻找它们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和它们产生的胰岛素+细胞将对我们未来在体外和体内产生新的β细胞的能力产生重要影响。