Genetic control of mature beta cell function and identity

项目摘要/摘要 功能成熟的β细胞对血糖稳态是必不可少的，它们的丧失或功能障碍是所有 糖尿病的类型。近年来，很明显，并不是所有的贝塔细胞都永久性地消失在 任何一种类型的糖尿病。相反，长期应激的β细胞失去了功能成熟的表型， 在一个称为去分化的过程中转变为功能失调状态。预防或逆转胰岛β细胞变性 分化是恢复糖尿病患者功能成熟的β细胞团的一种很有前途的方法。我们 最近发现了五个新的基因调控网络，我们假设它们对调控- ING成熟的β细胞的功能和特性。这项提案的总体目标是建立上述五个 调控网络作为控制β细胞功能和身份的新的遗传和药理学开关。 泰。在目标1中，我们将通过确定直接和间接受监管的节点来详细映射每个网络 每个监管者。我们将进一步确定网络的蜂窝功能，并寻找上游信号通路 预测会影响网络在人类和小鼠β细胞中的行为，以及它们的扰动点 在β细胞去分化过程中。在目标2中，我们将检验五种预测的调控因子对β细胞的因果关系。 利用遗传小鼠模型在体外原代小鼠和人胰岛以及体内的功能和身份 如果可以的话。我们将进一步测试遗传干预点在网络中锁定地点的效果。 在不同的非生理性应激下的真实的β细胞特性。

Project Summary/Abstract Functionally mature beta cells are essential to glucose homeostasis and their loss or dysfunction underlies all types of diabetes mellitus. In recent years, it has become clear that not all beta cells are permanently lost in either type of diabetes. Instead, chronically stressed beta cells lose their functionally mature phenotype and shift to a dysfunctional state in a process called de-differentiation. Preventing or reversing beta cell de- differentiation represents a promising approach to restoring functionally mature beta cell mass in diabetics. We have recently identified five novel genetic regulatory networks that we hypothesize to be important for regulat- ing mature beta cell function and identity. The overarching goal of this proposal is to establish the above five regulatory networks as novel genetic and pharmacological switches for controlling beta cell function and identi- ty. In Aim 1, we will map in detail each of the networks by determining direct and indirect regulated nodes for each regulator. We will further identify the networks' cellular function and find upstream signaling pathways predicted to affect the networks' behavior in both human and mouse beta cells, and their points of perturbation during beta cell de-differentiation. In Aim 2, we will test the causality of the five predicted regulators on beta cell function and identity in vitro in primary mouse and human islets, and in vivo, using genetic mouse models where available. We will further test the effect of genetic intervention points in the networks to lock in place ma- ture beta cell identity under the different diabetogenic stresses.