Achieving Productive Beta-cell Proliferation

1型糖尿病（T1D）是一种自身免疫性疾病，其特征是胰岛β细胞被破坏，导致胰岛素缺乏和高血糖。2型糖尿病（T2D）始于胰岛素抵抗，随后是β细胞衰竭。促进功能性β细胞的再生被认为是1型和2型糖尿病患者血糖控制正常化的一种有前途的治疗途径。再生是一个控制细胞增殖和分化的过程，恢复整个组织。虽然分化在成人胰腺再生中的作用仍然存在争议，但β细胞增殖的作用已经得到了很好的证实。因此，触发β细胞增殖被认为是糖尿病再生治疗的一种很有前途的方法。然而，有效再生的一个重要先决条件是β细胞增殖是生产性的，即细胞周期的进入导致β细胞数量的相应增加。值得注意的是，在绝大多数情况下，迫使β细胞进入细胞周期并不会导致β细胞质量的增加，这表明进入细胞周期可能是无效的。因此，确定我们驱动β细胞重新进入细胞周期的能力与未能实现有效β细胞质量扩增之间差异的基本原理是β细胞再生的一个重要且未被探索的挑战。在我们的建议中，我们将实现能够触发生产性β细胞增殖的杰出目标。为此，我们将首先在斑马鱼和小鼠β细胞中使用最先进的报告细胞识别非生产性增殖的细胞和分子参与者。其次，我们将通过在斑马鱼、小鼠和人类β细胞中过表达或突变这些基因来进行功能验证。最后，我们将定义β细胞保护非生产性β细胞增殖的药理学手段和代谢手段。总而言之，我们将应用三种不同的模型，包括斑马鱼，老鼠和人类来解决这个领域的一个突出问题。

Type 1 diabetes (T1D) mellitus is an autoimmune disease characterized by the destruction of beta-cells in the pancreatic islets, leading to insulin deficiency and hyperglycemia. Type 2 diabetes (T2D) commences with insulin resistance followed by beta-cell failure. Promoting the regeneration of functional beta-cells is recognized as a promising therapeutic avenue towards normalizing glycemic control in both type 1 and 2 diabetics. Regeneration is a process of controlled cell proliferation and differentiation that restores the entire tissue. While the role of differentiation in adult pancreas regeneration remains controversial, the role of beta-cell proliferation is well established. Thus, triggering beta-cell proliferation is considered a promising approach for regenerative therapy in diabetes. However, an important prerequisite for effective regeneration is that beta-cell proliferation is productive i.e. cell-cycle entry leads to a corresponding increase in beta-cell number. Notably, in the vast majority of cases, forcing cell-cycle entry in the beta-cells does not translate into increased beta-cell mass, indicating that cell-cycle entry might be unproductive. Thus, identifying the basic principles underlying the discrepancy between our ability to drive cell-cycle re-entry of beta-cells and the failure to achieve effective beta-cell mass expansion is an important and unexplored challenge for beta-cell regeneration. In our proposal, we will achieve the outstanding aim to be able to trigger productive beta-cell proliferation. To this, we will first identify the cellular and molecular players underlying unproductive proliferation using state-of-the art reporters in zebrafish and mouse beta-cells. Second, we will perform functional validation by overexpressing the genes or mutating them in zebrafish, mouse and human beta-cells. Finally, we will define pharmacological means and metabolic means for beta-cell protection from unproductive beta-cell proliferation. All in all, we will apply three different models, including zebrafish, mouse and human to address an outstanding question in the field.