Graduation Date

5-2020

Document Type

Master's Thesis

Degree

Master of Science

Program

Biological Science

Program Director

Meredith Protas, PhD

First Reader

Pankaj Kapahi, PhD

Second Reader

Ian Barr, PhD

Abstract

Reactive a-dicarbonyls (a-DC’s), such as methylglyoxal (MGO), are unavoidable metabolites generated during glycolysis that accumulate with age and have been linked with chronic age-related metabolic diseases such as Diabetes Mellitus. Diabetes Mellitus is generally characterized by peripheral neuropathy and sustained hyperglycemia. Chronic hyperglycemia leads to an increase in glycolysis and a downstream increase in reactive a-DC’s. The human body has a natural method of detoxifying these a-DC’s. Glycolytic cells have enzymes which can detoxify a-DC’s, but if overwhelmed, a-DC’s can accumulate and react non-enzymatically with proteins, lipids and DNA to yield a group of molecules called advanced glycation end-products (AGEs). A Caeonorhabditis elegans model, used to study the effects of a-DC accumulation, has paved the way for a study which has aimed to mitigate a-DC stress in a vertebrate model. Here we propose that the accumulation of AGEs in vivo enhances the likelihood of physiological phenotypes associated with age-related metabolic diseases such as diabetes. We propose that we are able to reduce metabolic disorder phenotypes, partly through activation of the conserved TRPA-1 ion channel, and the metabolic NAD+ salvage pathway, and rescue their pathological effects in a type II diabetic mouse model through drug interventions. Reconstituting the idea that AGEs are sufficient to cause adverse behavioral and physiological metabolic complications is necessary in establishing a novel target for drug treatment. Instituting a successful mouse model of drug-induced a-dicarbonyl detoxification could lead to human clinical trials for alternative diabetic treatments, and a reduction in secondary diabetic complications.

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