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-细胞蛋白分泌受损和β细胞质量降低引起的 与未能维持β细胞身份的情况联系在一起。 在这方面，非功能性内分泌样细胞。 在疾病修饰方面最重要的。 （ALHD1A3）已被发现是糖尿病小鼠和人T2D中β细胞去分化的标记 pancreata DB/DB小鼠显示出与A+ B细胞数量显着减少相关的葡萄糖对照改善。 ALDH1A3表达与β细胞功能之间的强相关性表明ALDH1A3大于 标记物并可能在糖尿病计划期间在β细胞推断中起作用。 尚不清楚，在配对下，A+细胞数的下降是否是由于正常B细胞​​的逆转而导致的 表型，死亡或新β细胞的出现。 以及如何逆转β细胞的失败。 一个研究aldh1a3在去分化β细胞中的作用 调查配对过程中表达AldH1A3（A+）细胞的命运（Aldh1a3 Creert敲击谱系 - 跟踪）。 （A-）具有恢复β细胞功能的细胞。 ALDH1A3抑制剂以查看ALDH1A3封锁是否会逆转β细胞衰竭。 在此应用中，她将测试遗传和药理学ALDH1A3的潜在治疗作用 糖尿病在体内的抑制及其作用机理（AIM 1）。 模型，Shiru直接测试糖尿病小鼠配对条件下β细胞去分化的可逆性 在用ALDH1A3抑制剂KOTX1和GA11的治疗中（AIM 2）。 成功的结合证明了aldh1a3在β细胞功能中的作用 T2D的病理生理过程。 潜在的治疗靶标在降低β细胞去分化/衰竭治疗T2D方面的潜在治疗靶标。