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？-成人胰腺细胞再生。在之前英国广播公司的资助下我们开发了一种完全或部分可诱导的转基因模型？-细胞消融（RIP-DTR）。在这些老鼠身上？-细胞再生发生在接近全？-细胞损失，这依赖于成人成熟细胞的转分化？-细胞间？-细胞间在这个提案中，我们将测试，在不同的方面中，i)是否？通过促进观察到的自发？-to-？细胞转换。？-细胞再生发生在？-细胞复制在其他糖尿病模型中较不严重？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？（这些小鼠的细胞消融）。因此,?-细胞再生主要发生在RIP-DTR小鼠中，其机制是？细胞重新编程。我们的目标之一是确定年龄是否在？-细胞再生/ ？-细胞重编程，因为在老年啮齿动物和人类中，胰岛的增殖已被证明会急剧下降。此外，我们将研究控制？-到？- RIP-DTR小鼠的细胞转分化。这些分析将与以下研究并行进行：iii)探索细胞命运重编程是否是不同成年胰腺细胞类型的共同特征，并且不限于？-仅限细胞。new的异种起源？-细胞特别有趣，因为几乎完成了？在RIP-DTR小鼠中实现的细胞耗竭重现了与1型糖尿病患者非常相似的情况。

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.