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

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.