Beta Cell Regeneration by Reprogramming of Adult Pancreatic Cells

描述(由申请人提供)：本提案的总体目标是确定改善成人胰腺细胞再生的方法。在以前的BCBC资助下，我们发展了一种可诱导的完全或部分？细胞消融的转基因模型(RIP-DTR)。在这些小鼠中，β细胞的再生发生在几乎全部的β细胞丧失之后，这依赖于成年成熟的β细胞向β细胞的转分化。在这项建议中，我们将测试，在不同的方面，i)是否可以通过促进观察到的自发细胞到细胞的转化来增强RIP-DTR小鼠的？细胞再生。在其他不太严重的糖尿病模型中，细胞再生是通过细胞复制来实现的。RIP-DTR小鼠的再生效率低于这些小鼠模型，可能是因为DT处理几乎没有留下？-细胞(DT代表白喉毒素，用于诱导这些小鼠的？-细胞消融)。因此，在RIP-DTR小鼠中，主要通过？-细胞重新编程的机制进行？-细胞再繁殖。我们的目标之一将是确定年龄是否在β-细胞再生/？-细胞重编程中起作用，因为在老年啮齿类动物和人类中，胰岛的增殖已被证明显著下降。此外，我们还将研究控制RIP-DTR小鼠转分化的分子机制。这些分析将与旨在探索细胞命运重编程是否是不同类型成人胰腺细胞的共同特征，而不仅仅限于？细胞的研究同时进行。新的？-细胞的异源来源特别有趣，因为在RIP-DTR小鼠中实现的几乎完全的？-细胞耗尽重建了与在1型糖尿病患者中发现的情况非常相似的情况。 公共卫生相关性：了解-细胞再生的机制并确定促进-细胞的形成和/或生长和/或存活的细胞和因子(S)应该对人类T1D新疗法的开发有很大的影响。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to identify means for improving ?-cell regeneration in the adult pancreas. With previous BCBC funding we have developed a transgenic model of inducible total or partial ?-cell ablation (RIP-DTR). In these mice, ?-cell regeneration occurs after near total ?-cell loss, and this relies on the transdifferentiation of adult mature ?-cells to ?-cells. In this proposal we will test, among different aspects, i) whether ?-cell regeneration in RIP-DTR mice can be enhanced by promoting the observed spontaneous ?-to-?-cell conversion. ?-cell regeneration occurs by ?-cell replication in other diabetes models of less severe ?-cell ablation. Regeneration in RIP-DTR mice is less efficient than in these mouse models probably because DT treatment leaves almost no ?-cells (DT stands for diphtheria toxin, the agent used to induce ?-cell ablation in these mice). Accordingly, ?-cell repopulation principally occurs in RIP-DTR mice by a mechanism of ?-cell reprogramming. One of our objectives will be ii) to determine if age plays a role in ?-cell regeneration / ?-cell reprogramming , since proliferation in islets has been shown to profoundly decline in older rodents and humans. In addition, we will examine the molecular mechanisms controlling ?- to ?-cell transdifferentiation in RIP-DTR mice. These analyses will be performed in parallel with studies aimed at iii) exploring whether cell fate reprogramming is a common feature of different adult pancreatic cell types, and is not restricted to ? - cells only. The heterologous origin of new ?-cells is particularly interesting, since the almost complete ?-cell depletion achieved in RIP-DTR mice recreates a condition very similar to the situation found in Type 1 diabetic patients. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms of ?-cell regeneration and identifying the cells and factor(s) that enhance the formation and/or growth and/or survival of ?-cells should have a high impact on the development of new treatments for human T1D.