Thesis

Role of trpv4 in prediabetic obese nerves

There are 86 million people with prediabetic obesity that are susceptible to type II diabetes. Prediabetes is characterized by higher than average blood sugar levels and depending on the severity, may lead to a number of problems in various tissue types. Prediabetes has been shown to induce complications in the peripheral nervous system (PNS), which is a common result of diabetes. Recent studies have shown an upregulation of transient receptor potential vanilloid 4 (TRPV4), a channel that senses a range of stimuli, in nerves with induced peripheral neuropathies. Also, it has been reported that mutations in the TRPV4 gene causes neurological disorders. In my project, I examined the effects of TRPV4 modulating drugs on the nerves of diet-induced prediabetic mice. Six-week-old C57BL6/J mice were placed on a 60% high fat or 10% control diet for 19 weeks. Blood glucose and weight measurements were then used to determine the prediabetic condition. Sciatic nerves and dorsal root ganglia (DRG) from these animals were extracted for protein, then quantified with the BCA kit. Once protein concentrations were measured, proteins were tested using western blot and ELISA. Hematoxylin and eosin stains were also used to visualize changes in the epidermal thickness of experimental groups. Animals fed a high fat diet (HFD) weighed substantially more and displayed elevated blood glucose levels than mice on the control diet. Surgery of the drug pump heightened sensitivity for animals on a high fat diet. Antagonist treatment significantly reduced body weight of the HFD mice. The motor coordination test showed poor results among agonist dosed HFD mice. The sciatic nerves and DRG of dosed HFD mice did not indicate change in TRPV4 levels nor IL-6 levels. This suggests that the TRPV4 modulators are not significantly altering the quantity of the channel nor initiating inflammatory response within the prediabetic obese nerve. In contrast, the antagonist's role in weight-loss of diet-induced prediabetic obese mice demonstrates its potential as a candidate for future studies.

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