Pancreatic Intra-Islet Ducts

胰岛内导管

基本信息

项目摘要

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):更好地理解如何形成新的细胞,以及它们可能从哪里产生,对于我们设计糖尿病患者的细胞替代疗法策略的目标至关重要。细胞复制似乎是年轻健康动物(或许也包括人类)产生新细胞的主要机制。然而,新生- 细胞从非?β-细胞来源也可能发挥重要作用,特别是在糖尿病患者和老年人中,其中β-细胞复制的能力似乎减弱。我们认为胰管已经成为新的非细胞来源的最有可能的候选者。胰管和胰岛之间的解剖学“关联”已被充分描述超过100年,其中大多数胰岛显示出与胰管的某种接触或至少接近胰管。然而,在这里,在一个基因改变的小鼠模型中,在部分胰腺切除术后,细胞不增殖,我们描述了一个相当戏剧性的发芽新的导管结构从现有的大导管部分胰腺切除术后。这些发芽的导管在胰岛内生长并分叉。初步实验强烈表明,这些胰岛内导管细胞转化为胰岛细胞。如果这些小鼠在胰腺切除术后恢复胰岛细胞增殖的背景下繁殖,则这种导管生长在很大程度上受到抑制。此外,我们发现胰岛侵入导管通常在年轻小鼠和年轻人中短暂存在,首次出现在大约两周龄的小鼠中,但在八周龄后几乎完全消失。在那里(至少在小鼠中),我们再次发现年轻小鼠中的这些导管细胞产生新的胰岛素+细胞。在这个建议中,我们将首先努力描述这些胰岛内导管结构出现的过程,特别是在它们出现的规则导管网络内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。本分析的一部分将考虑这些导管结构来自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,不仅确定其精确的表型, 也在寻找它们是如何从导管细胞中产生的线索。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+细胞将对我们将来在体外和体内产生新的胰岛细胞的能力产生重要影响。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
PNA lectin for purifying mouse acinar cells from the inflamed pancreas.
  • DOI:
    10.1038/srep21127
  • 发表时间:
    2016-02-17
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Xiao X;Fischbach S;Fusco J;Zimmerman R;Song Z;Nebres P;Ricks DM;Prasadan K;Shiota C;Husain SZ;Gittes GK
  • 通讯作者:
    Gittes GK
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GEORGE K. GITTES其他文献

GEORGE K. GITTES的其他文献

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{{ truncateString('GEORGE K. GITTES', 18)}}的其他基金

Alpha cell conversion to beta cells in non-human primates
非人灵长类动物中α细胞转化为β细胞
  • 批准号:
    10451657
  • 财政年份:
    2018
  • 资助金额:
    $ 33.5万
  • 项目类别:
Alpha cells conversion to beta cells in non-human primates
非人类灵长类动物中的α细胞转化为β细胞
  • 批准号:
    9789262
  • 财政年份:
    2018
  • 资助金额:
    $ 33.5万
  • 项目类别:
Alpha cell conversion to beta cells in non-human primates
非人灵长类动物中α细胞转化为β细胞
  • 批准号:
    10200032
  • 财政年份:
    2018
  • 资助金额:
    $ 33.5万
  • 项目类别:
Endogenous alpha-to-beta cell transdifferentiation in diabetes
糖尿病中的内源性α-β细胞转分化
  • 批准号:
    9899977
  • 财政年份:
    2017
  • 资助金额:
    $ 33.5万
  • 项目类别:
EGF and TGF-β signaling synergy in β-cell proliferation
EGF 和 TGF-β 信号在 β 细胞增殖中的协同作用
  • 批准号:
    9349505
  • 财政年份:
    2016
  • 资助金额:
    $ 33.5万
  • 项目类别:
Pancreatic Intra-Islet Ducts
胰岛内导管
  • 批准号:
    8626586
  • 财政年份:
    2013
  • 资助金额:
    $ 33.5万
  • 项目类别:
Smad regulation of pancreatic islet formation
Smad 调节胰岛形成
  • 批准号:
    7632442
  • 财政年份:
    2009
  • 资助金额:
    $ 33.5万
  • 项目类别:
Smad Regulation of Pancreatic Islet Formation
Smad 调节胰岛形成
  • 批准号:
    8277292
  • 财政年份:
    2009
  • 资助金额:
    $ 33.5万
  • 项目类别:
Smad Regulation of Pancreatic Islet Formation
Smad 调节胰岛形成
  • 批准号:
    8080424
  • 财政年份:
    2009
  • 资助金额:
    $ 33.5万
  • 项目类别:
Smad Regulation of Pancreatic Islet Formation
Smad 调节胰岛形成
  • 批准号:
    7905063
  • 财政年份:
    2009
  • 资助金额:
    $ 33.5万
  • 项目类别:

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