Buck Institute for Research on Aging

Role of Advanced Glycation Endproducts in Aging and Neurodegeneration

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Aging diabetics often develop serious health complications such as neuropathic pain, renal failure, heart disease, increased risk for neurodegenerative diseases, etc. Interestingly, studies show that glucose is not the main culprit behind these complications, rather, prolonged hyperglycemia results in the accumulation of reactive α-dicarbonyl compounds (α-DCs). α-DCsreacts to irreversibly damage essential proteins, lipids, and DNA, which ultimately leads to the pathologies associated with diabetes. A major bottleneck in understanding the biochemistry behind α-DC-stress, is the lack of genetic models that could recapitulate effects of α-DCs rapidly. To bridge this gap, we have established a Caenorhabditis elegans (worm) model that mimic molecular and physiological phenotypes associated α-DC-stress. Using this model, we found a conserved ion channel, TRPA1 that acts as a sensor for α-DCs; we further show that TRPA1 can be a bona fide drug target in diabetes. In this proposed work, I am leveraging the worm model as a powerful genetic system to understand the underlying mechanism of how TRPA1may protect against α-DC-stress. The goal is to identify novel enzyme targets (e.g. interactors of TRPA1), required for preventing α-DC accumulation. Ultimately, we wish to identify new therapeutics to counter α-DC-stress that would be relevant for various diabetic complications