Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of beta cell failure

项目摘要 2型糖尿病（T2 D）是由β细胞胰岛素分泌受损和β细胞质量减少引起的。两个特征 与β细胞的特性无法维持有关。结果，功能性β细胞去分化为 非功能性内分泌祖细胞样细胞。在这方面，β细胞去分化是否可逆是一个 最重要的概念之一。醛脱氢酶1亚型A3 已发现ALHD 1A 3是糖尿病小鼠和人T2 D中β细胞去分化的标志物 胰腺ALDH 1A 3阳性β（A+）细胞已显示功能缺陷。此外， db/db小鼠表现出与A+ B细胞数量显著减少相关的改善的葡萄糖控制。 ALDH 1A 3表达和β细胞功能之间的强相关性表明ALDH 1A 3比β细胞功能更重要。 是一种标记物，也可能在糖尿病进展期间的β细胞去分化中起作用。再者是 不知道配对喂养下A+细胞数量的减少是否是由于逆转为正常的B细胞 表型、死亡或新β细胞的出现。回答这些问题将提供线索， 以及如何逆转β细胞衰竭。因此，PI首先建立了两种动物模型来解决这些问题： 一个研究ALDH 1a 3在去分化β细胞（β细胞特异性Aldh 1a 3敲除）中的作用，另一个研究ALDH 1a 3在去分化β细胞（β细胞特异性Aldh 1a 3敲除）中的作用。 为了研究ALDH 1A 3-表达（A+）细胞在配对饲养期间的命运（ALDH 1A 3 Creert敲入谱系- 跟踪）。后一种模型将使她能够解决A+细胞是否转化回ALDH 1A 3阴性 (A-)恢复β细胞功能的细胞。为了补充这些模型，PI还将使用选择性化学品 ALDH 1A 3抑制剂，看看ALDH 1A 3阻断是否可以逆转β细胞衰竭。 在这项应用中，她将测试基因和药理学ALDH 1A 3的潜在治疗效果。 抑制体内糖尿病及其作用机制（目的1）。使用ALDH 1A 3谱系追踪小鼠 模型，她将直接测试在成对喂养条件下糖尿病小鼠中β细胞去分化的可逆性， 在ALDH 1A 3抑制剂、KOTX 1和GA 11的治疗中（目的2）。 本申请的成功完成将证明ALDH 1A 3在β细胞功能中的作用， T2 D的病理生理过程。更重要的是，拟议的工作将评估ALDH 1A 3是否是一种 通过逆转β细胞去分化/衰竭治疗T2 D的潜在治疗靶点。

Project Summary Type 2 diabetes (T2D) is caused by impaired β-cell insulin secretion and reduced β-cell mass. Both features have been linked to the failure to maintain β-cell identity. As a result, functional β-cell cells dedifferentiate into non-functional endocrine progenitor-like cells. In this regard, whether β-cell dedifferentiation is reversible is one of the most important notions in terms of disease modification. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) has been discovered as a marker of β-cell dedifferentiation in diabetic mice and human T2D pancreata. ALDH1A3-positive β (A+) cells have been shown to be functionally defective. Moreover, pair-fed db/db mice showed improved glucose control associated with a significant decrease in the number of A+ b cells. The strong correlation between ALDH1A3 expression and β-cell function suggests that ALDH1A3 is more than a marker and may also plays a role in β-cell dedifferentiation during diabetes progression. Furthermore, it is unknown whether the decrease in A+ cell number under pair-feeding was due to reversal to a normal b-cell phenotype, death, or the emergence of new β cells. Answering these questions will provide clues on whether and how β-cell failure can be reversed. Thus, the PI first established two animal models to address these queries: one to investigate the role of ALDH1A3 in dedifferentiating β cells (β-cell specific Aldh1a3 knockout) and another to investigate the fate of ALDH1A3-expressing (A+) cells during pair-feeding (ALDH1A3 Creert knock-in lineage- tracing). The latter model will allow her to address whether A+ cells are converted back into ALDH1A3-negative (A-) cells with restored β-cell function. To complement these models, the PI will also use selective chemical ALDH1A3 inhibitors to see if ALDH1A3 blockade can reverse β-cell failure. In this application, she will test the potential therapeutic effects of genetic and pharmacological ALDH1A3 inhibition in diabetes in vivo and its mechanism of action (Aim 1). Using an ALDH1A3 lineage tracing mouse model, she will directly test the reversibility of β-cell dedifferentiation in diabetic mice in pair-fed condition, and in the treatment with ALDH1A3 inhibitors, KOTX1 and GA11 (Aim 2). The successful completion of this application will demonstrate the role of ALDH1A3 in β-cell function in the pathophysiological process of T2D. More importantly, the proposed work will assess whether ALDH1A3 is a potential therapeutic target in the treatment of T2D by reversing β-cell dedifferentiation/failure.