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进的方法？-在成年胰腺中的细胞再生。在之前的BCBC资助下，我们已经开发了一种诱导性全部或部分？细胞消融（RIP-DTR）。在这些小鼠中，？-细胞再生发生后，几乎全部？-细胞损失，这依赖于成年成熟？细胞？细胞在本建议中，我们将在不同方面中测试：i）是否？RIP-DTR小鼠的细胞再生可以通过促进观察到的自发性？去-？-细胞转化?-细胞再生发生在？在其他糖尿病模型中的细胞复制不太严重？细胞消融RIP-DTR小鼠的再生效率低于这些小鼠模型，可能是因为DT治疗几乎没有留下？细胞（DT代表白喉毒素，用于诱导？这些小鼠中的细胞消融）。因此，？RIP-DTR小鼠的细胞再增殖主要通过以下机制进行：细胞重编程我们的目标之一将是ii）确定年龄是否在？细胞再生细胞重编程，因为在老年啮齿动物和人类中，胰岛的增殖已经显示出显著下降。此外，我们还将研究控制？什么？RIP-DTR小鼠的细胞转分化。这些分析将与旨在iii）探索细胞命运重编程是否是不同成人胰腺细胞类型的共同特征的研究平行进行，并且不限于？- 只有细胞。新的异源起源？细胞是特别有趣的，因为几乎完全？RIP-DTR小鼠中实现的细胞耗尽重现了与1型糖尿病患者中发现的情况非常相似的状况。 公共卫生相关性：了解？细胞再生和识别细胞和因子，增强形成和/或生长和/或生存？细胞应该对人类T1 D新疗法的开发产生重大影响。

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.