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.

项目概要 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。两者都有特点 与无法维持 β 细胞身份有关。结果，功能性β细胞去分化为 无功能的内分泌祖细胞样细胞。就此而言，β细胞去分化是否可逆是一个问题。 疾病修饰方面最重要的概念。醛脱氢酶 1 亚型 A3 (ALHD1A3) 被发现是糖尿病小鼠和人类 T2D 中 β 细胞去分化的标志物 胰腺。 ALDH1A3 阳性 β (A+) 细胞已被证明存在功能缺陷。此外，配对喂养 db/db 小鼠的血糖控制得到改善，且 A+ b 细胞数量显着减少。 ALDH1A3 表达与 β 细胞功能之间的强相关性表明 ALDH1A3 比 一种标记物，也可能在糖尿病进展过程中的 β 细胞去分化中发挥作用。此外，它是 未知配对喂养下 A+ 细胞数量的减少是否是由于逆转为正常 B 细胞所致 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 首先建立了两个动物模型来解决这些问题： 一个研究 ALDH1A3 在去分化 β 细胞中的作用（β 细胞特异性 Aldh1a3 敲除），另一个研究 研究配对喂养期间表达 ALDH1A3 (A+) 的细胞的命运（ALDH1A3 Creert 敲入谱系- 追踪）。后一个模型将帮助她解决 A+ 细胞是否会转回 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 ALDH1A3 阻断是否可以逆转 β 细胞衰竭。 在此应用中，她将测试遗传和药理学 ALDH1A3 的潜在治疗效果 体内对糖尿病的抑制作用及其作用机制（目标1）。使用 ALDH1A3 谱系追踪小鼠 模型中，她将直接测试配对喂养条件下糖尿病小鼠β细胞去分化的可逆性，以及 ALDH1A3 抑制剂、KOTX1 和 GA11 治疗（目标 2）。 该应用的成功完成将证明 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 通过逆转 β 细胞去分化/衰竭来治疗 T2D 的潜在治疗靶点。