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

ALDH1A3 的遗传和药理学抑制可治疗 β 细胞衰竭

• 批准号: 10572377
• 负责人: Jinsook Son
• 金额: $ 15.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572377
• 关键词: Ablation; Address; Animal Model; Apoptosis; B-Lymphocytes; Back; Beta Cell; Cell Count; Cell Separation; Cell physiology; Cells; Cessation of life; Characteristics; Chemicals; Complement; Diabetes Mellitus; Diabetic mouse; Disease; Endocrine; Failure; Functional disorder; Gene Expression; Generations; Genetic; Genetic Transcription; Human; Impairment; In Vitro; Insulin; Knock-in; Knock-out; Knockout Mice; Knowledge; Link; Modeling; Modification; Mus; NR2F6 gene; Non-Insulin-Dependent Diabetes Mellitus; Phenotype; Play; Process; Protein Isoforms; RXRA gene; Regulation; Role; Structure of beta Cell of islet; Testing; Therapeutic; Therapeutic Effect; Work; aldehyde dehydrogenase 1; blood glucose regulation; cell dedifferentiation; db/db mouse; diabetic; feeding; functional restoration; genetic approach; glucose tolerance; improved; in vivo; inhibitor; insulin secretion; islet; knockout animal; metabolic phenotype; mouse model; novel therapeutic intervention; pharmacologic; progenitor; stem; success; therapeutic target

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.

项目摘要 2型糖尿病(T2D)是由β细胞胰岛素分泌受损和β细胞质量减少引起的。这两个功能 与未能保持β细胞身份有关。结果，功能正常的β细胞去分化为 无功能的内分泌祖细胞样细胞。在这一点上，β细胞去分化是否可逆是其中之一 在疾病改良方面的最重要的概念。乙醛脱氢酶1亚型A3 (ALHD1A3)已被发现是糖尿病小鼠和人类T2D中β细胞去分化的标志 胰腺。ALDH1A3阳性的β(A+)细胞被证明是有功能缺陷的。此外，配对喂养 Db/db小鼠表现出血糖控制的改善与A+b细胞数量的显著减少相关。 ALDH1A3的表达与β细胞功能的相关性很强，提示ALDH1A3的表达不止于 这是一种标志物，也可能在糖尿病进展过程中β细胞去分化过程中发挥作用。此外，它是 尚不清楚配对喂养下A+细胞数量的减少是否是由于反转到正常的B细胞 表型、死亡或出现新的β细胞。回答这些问题将提供线索，说明 以及如何扭转β-cell故障。因此，PI首先建立了两个动物模型来解决这些问题： 一个是研究ALDH1A3在β细胞去分化中的作用(β细胞特异性的ALDH1A3基因敲除)，另一个是研究ALDH1A3基因敲除 研究表达ALDH1A3的(A+)细胞在配对喂养(ALDH1A3 Creert敲入谱系--)过程中的命运 跟踪)。后一种模型将允许她解决A+细胞是否转换回ALDH1A3阴性的问题 (a-)β细胞功能恢复的细胞。为了补充这些模型，PI还将使用选择性化学物质 ALDH1A3抑制剂，看看阻断ALDH1A3是否可以逆转β细胞衰竭。 在这项应用中，她将测试遗传和药理学ALDH1A3的潜在治疗效果 体内抑制糖尿病及其作用机制(目标1)。使用ALDH1A3谱系追踪小鼠 模型，她将直接测试糖尿病小鼠在配对喂养条件下β细胞去分化的可逆性，以及 在ALDH1A3抑制剂治疗中，KOTX1和GA11(目标2)。 本申请的成功完成将证明ALDH1A3在β细胞功能中的作用。 T2D的病理生理过程。更重要的是，拟议的工作将评估ALDH1A3是否是一种 逆转β细胞去分化/衰竭治疗T2D的潜在治疗靶点