Regulation of beta cell identity and dedifferentiation

维持β细胞健康对1型和2型糖尿病都有重要意义。β细胞内的内在变化对这些需要患者终身管理的衰弱性疾病的发生和进展有影响。几十年的研究已经确定了从胚胎祖细胞产生β细胞所必须发生的事件的音乐会，主要使用啮齿动物模型，并且删除这些调节因子中的几个会消除内分泌，特别是β细胞，群体。在这里，我们使用复杂的转基因小鼠模型和人类干细胞衍生的β细胞的组合来识别维持胰岛素产生细胞功能的关键信号。该提案的总体目标是阐明转录因子Sox 9的新功能，目前认为该转录因子仅在胰腺祖细胞和成人外分泌管和中央腺泡细胞中具有活性。与另一种转录因子Ngn 3类似，我们的数据表明Sox 9在成熟β细胞中以低水平表达，在那里它执行关键功能。Sox 9丢失的后果不如在消除已知导致年轻人糖尿病成熟发作（MODY）的因素后观察到的那些严重，因此反映了人类2型糖尿病的现实，其中许多缺陷最终导致β细胞功能障碍的发展。我们认为Sox 9在调节β细胞发育和功能的重要方面起着核心作用。 在第一个具体目标中，我们建议确定Sox 9在成熟啮齿动物和人类β细胞中消除的后果。我们的初步数据表明，Sox 9的低水平表达支持β细胞特性，转录因子的丢失促进β细胞功能障碍。在第二个具体目标中，我们将研究β细胞中强制Sox9表达的后果，目的是定义由转录因子控制的调控网络。我们预计，从β细胞中具有超生理水平Sox 9的转基因小鼠中挖掘数据将使我们能够为以前不知道会影响β细胞功能的蛋白质分配新的角色。在第三个具体目标中，我们专注于Sox 9调节β细胞功能的机制。我们的初步数据表明，Sox 9调节初级纤毛的形成和功能，初级纤毛是一种已知调节β细胞活性的细胞器。总之，我们预计本提案中概述的实验将提供对维持β细胞适当和精确功能的调节网络的更深入理解。揭示β细胞衰竭背后的原因应该提供新的见解，可以利用这些见解来设计治疗糖尿病患者的新治疗策略。

Maintenance of beta cell health has significant implications for Diabetes, both Type 1 and Type 2. Intrinsic changes within the beta cell have an impact on the initiation and progression of these debilitating diseases that require life-long management by the patient. Decades of research has identified the concert of events that must occur to generate a beta cell from embryonic progenitors, primarily using rodent models, and deletion of several of these regulators ablates endocrine, and specifically beta cell, populations. Here, we use a combination of sophisticated transgenic mouse models and human stem cell-derived beta cells to identify critical signals that maintain function in insulin producing cells. The overarching goal of this proposal is to elucidate novel functions of the transcription factor Sox9, currently believed to be only active in pancreas progenitors and adult exocrine duct and centroacinar cells. Similar to another transcription factor, Ngn3, our data indicate that Sox9 is expressed at low levels in mature beta cells where it performs critical functions. The consequences of Sox9 loss are less severe that those observed upon elimination of factors known to result in maturity onset of diabetes in the young (MODY), thus reflecting the reality of human Type 2 Diabetes, in which numerous defects culminate in the development of beta cell dysfunction. We pose that Sox9 plays a central role in regulating essential aspects of beta cell development and function. In the first specific aim, we propose to determine the consequences of Sox9 elimination in mature rodent and human beta cells. Our preliminary data demonstrate that low-level expression of Sox9 supports beta cell properties and loss of the transcription factor promotes beta cell dysfunction. In the second specific aim, we will investigate the consequences of forced Sox9 expression in beta cells with the goal of defining the regulatory network controlled by the transcription factor. We anticipate that mining data from transgenic mice with supra-physiological levels of Sox9 in the beta cells will allow us to assign novel roles to proteins previously not known to influence beta cell function. In the third specific aim, we focus on the mechanisms by which Sox9 modulates beta cell function. Our preliminary data indicate that Sox9 regulates formation and thus function of primary cilia, a cellular organelle known to regulate beta cell activities. In summary, we anticipate that the experiments outlined in this proposal will provide a deeper understanding of regulatory networks that are in place to maintain the appropriate and precise functioning of a beta cell. Uncovering the reasons behind beta cell failure should provide novel insights that can be exploited to devise novel therapeutic strategies for the treatment of patients with Diabetes.