Sean S. Davies, Ph.D.
Investigates the role of lipid mediators in modulating physiological and pathophysiological processes
Our lab’s mission is to develop novel and highly sustainable therapeutic interventions for chronic diseases in order to improve human health. We do this by investigating the role of lipid mediators in modulating physiological and pathophysiological processes and then using this knowledge to design novel interventions to modulate these processes.
THERAPEUTIC MODIFICATION OF GUT MICROBIOTA
Recent studies have suggested a critical role for gut microbiota in human health. Difference in bacterial species associated with the gut appear to be causally linked to adiposity and insulin resistance, which have in turn been linked to oxidative stress and inflammation and eventual vascular disease. Because the exact species of bacteria and bacterial metabolites that modulate health are only now beginning to be elucidated, we have taken an alternative approach of genetically modifying bacterial species associated with the mammalian gut to produce therapeutic metabolites (small molecules like lipids and peptides) that reduce oxidative stress and inflammation in the host. We hypothesize this approach can be used as a novel drug delivery system for treating chronic disease. Our current research focus on two proof of concept therapeutic compounds: N-acyl phosphatidylethanolamine (NAPE) and an ApoAI mimetic peptide (4F). Excitingly, probiotic bacteria engineered to express high levels of NAPE protect against the development of obesity and glucose intolerance in mice fed a high-fat diet. We are exploring the mechanisms underlying this effect and the critical parameters for NAPE delivery and efficacy.
REACTIVE LIPID ALDEHYDES
Oxidative stress has been implicated in atherosclerosis, diabetes, neurodegenerative diseases, and various cancers. Peroxidation of lipids generates highly reactive aldehydes including malondialdehyde (MDA), acrolein, 4-hydroxynonenal, and isolevuglandins (IsoLG, also given trivial name of isoketals). These lipid aldehydes react with proteins and phosphatidylethanolamine (PE) to exert their effects.
We have developed small molecule primary amines that selectively scavenge IsoLG and closely related dicarbonyls. Because these scavenger only alter the levels of IsoLG and closely related dicarbonyl, they allow us to distinguish between the effects of IsoLG and other lipid aldehydes like 4-hydroxynonenal and acrolein, as well as non-reactive lipids like F2-isoprostanes and HETEs. Two of these aldehyde scavengers, salicylamine (alternatively named SAM, 2-hydroxylbenzylamine, or 2HOBA) and pentylpyridoxamine (PPM) have good DMPK characteristics and oral bioavailability so they can be used in animal models as well as in cultured cells. Excitingly, SAM protects against oxidant induced cytotoxicity, oxidant induce sodium channel inactivation, age-related neurodegeneration, angiotensin-induced hypertension, and rapid pacing induced amyloid oligmer formation.
Recently, we have begun studying the contribution of IsoLG and related dicarbonyls to HDL dysfunction, an important element to the development of atherosclerosis.
Exposure of vascular cells to these aldehydes results in endothelial dysfunction, secretion of inflammatory cytokines, and recruitment of monocytes, key steps in the initiation of inflammation. The inflammatory effects of lipid aldehydes have often been presumed to arise from their modification of proteins or DNA. However, recent studies have shown that many of these aldehydes also modify phosphatidylethanolamines(PE) and that PE modification increases under conditions associated with oxidative stress. These led us to hypothesize that these aldehyde-modified PE may play a critical role in inflammatory diseases associated with oxidative stress. Our lab is examining the molecular mechanisms of aldehyde-modified PE generation, how they exert their proinflammatory effects, and how they are inactivated by catabolic enzymes.