Overview

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 Bacteria

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 (Isolevuglandins/Isoketals)

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.

One difficulty in studying the contribution of reactive lipid aldehydes has been the lack of tools to isolate their effects from the myriad of other products formed by lipid peroxidation at the same time. Therefore, in order to determine the contribution of IsoLG to disease processes, we first had to develop the appropriate tools. These included mass spectrometric methods to measure the IsoLG-protein and IsoLG-PE adducts. We also developed a single-chain antibody that selectively recognized IsoLG-protein adducts that has been used by a number of our collaborators to localize sites of IsoLG-protein adduct formation in tissues and cultured cells. Perhaps most importantly, we 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.

Aldehyde-Modified Phosphatidylethanolamines

Exposure of vascular cells to these aldehydes results in endothelial dysfunction, secretion of inflammatory cytokines, and recruitment of 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.

 

 

Publications

Featured publications

  1. Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment. Dosoky NS, Chen Z, Guo Y, McMillan C, Flynn CR, Davies SS (2019) Appl Microbiol Biotechnol 103(16): 6711-6723
    › Primary publication · 31203417 (PubMed)
  2. Administration of N-Acyl-Phosphatidylethanolamine Expressing Bacteria to Low Density Lipoprotein Receptor Mice Improves Indices of Cardiometabolic Disease. May-Zhang LS, Chen Z, Dosoky NS, Yancey PG, Boyd KL, Hasty AH, Linton MF, Davies SS (2019) Sci Rep 9(1): 420
    › Primary publication · 30674978 (PubMed) · PMC6344515 (PubMed Central)
  3. Simplified LC/MS assay for the measurement of isolevuglandin protein adducts in plasma and tissue samples. Yermalitsky VN, Matafonova E, Tallman K, Li Z, Zackert W, Roberts LJ, Amarnath V, Davies SS (2019) Anal Biochem : 89-101
    › Primary publication · 30458125 (PubMed)
  4. Modification by isolevuglandins, highly reactive γ-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function. May-Zhang LS, Yermalitsky V, Huang J, Pleasent T, Borja MS, Oda MN, Jerome WG, Yancey PG, Linton MF, Davies SS (2018) J Biol Chem 293(24): 9176-9187
    › Primary publication · 29712723 (PubMed) · PMC6005447 (PubMed Central)
  5. Dietary Fatty Acids Control the Species of N-Acyl-Phosphatidylethanolamines Synthesized by Therapeutically Modified Bacteria in the Intestinal Tract. Dosoky NS, Guo L, Chen Z, Feigley AV, Davies SS (2018) ACS Infect Dis 4(1): 3-13
    › Primary publication · 29019649 (PubMed) · PMC6555640 (PubMed Central)
  6. Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D. Chen Z, Zhang Y, Guo L, Dosoky N, de Ferra L, Peters S, Niswender KD, Davies SS (2017) J Lipid Res 58(8): 1624-1635
    › Primary publication · 28596183 (PubMed) · PMC5538284 (PubMed Central)
  7. Determination of the Pharmacokinetics and Oral Bioavailability of Salicylamine, a Potent γ-Ketoaldehyde Scavenger, by LC/MS/MS. Zagol-Ikapitte I, Matafonova E, Amarnath V, Bodine CL, Boutaud O, Tirona RG, Oates JA, Roberts Ii LJ, Davies SS (2010) Pharmaceutics 2(1): 18-29
    › Primary publication · 27721340 (PubMed)
  8. Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts. Guo L, Chen Z, Amarnath V, Yancey PG, Van Lenten BJ, Savage JR, Fazio S, Linton MF, Davies SS (2015) Antioxid Redox Signal 22(18): 1633-45
    › Primary publication · 25751734 (PubMed) · PMC4485367 (PubMed Central)
  9. Reactive γ-ketoaldehydes promote protein misfolding and preamyloid oligomer formation in rapidly-activated atrial cells. Sidorova TN, Yermalitskaya LV, Mace LC, Wells KS, Boutaud O, Prinsen JK, Davies SS, Roberts LJ, Dikalov SI, Glabe CG, Amarnath V, Barnett JV, Murray KT (2015) J Mol Cell Cardiol : 295-302
    › Primary publication · 25463275 (PubMed) · PMC4302000 (PubMed Central)
  10. DC isoketal-modified proteins activate T cells and promote hypertension. Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J, Harrison DG (2014) J Clin Invest 124(10): 4642-56
    › Primary publication · 25244096 (PubMed) · PMC4220659 (PubMed Central)