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Clinical and Animal Studies of Lipid-Derived Protein Modifications in Autism, Kidney Dialysis, Keratitis and Age-Related Macular Degeneration

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Title: Clinical and Animal Studies of Lipid-Derived Protein Modifications in Autism, Kidney Dialysis, Keratitis and Age-Related Macular Degeneration
Author : Liang Lu
Release Date : January 18, 2013
Genre: Medical,Books,Professional & Technical,
Pages : * pages
Size : 28648 KB

Description

Lipid oxidation in diverse biological systems contributes to normal physiological processes and is increasingly believed to be associated with age-related diseases. Lipid oxidation products, e.g., isolevuglandins and ã-hydroxyalkenals, and their protein adducts are produced during and may even contribute to disease pathogenesis. This thesis reports clinical studies on the occurrence of 2-pentylpyrrole, iso[4]LGE2-protein adducts and carboxyethylpyrrole (CEP) protein modifications in brain and blood from autistic individuals, blood from hemodialysis patients, as well as cornea from a mouse model of keratitis. Similar levels of these modifications and autoantibodies against them were detected in blood from both autistic individuals and normal controls. Autistic patients born prematurely showed significantly elevated iso[4]LGE2-protein adduct levels. Oral supplementation with alpha tocopherol had no significant effect on levels of oxidative protein modifications in patients treated by hemodialysis, and thus, does not result in an antioxidant benefit in hemodialysis. We detected the formation of iso[4]LGE2- and LGE2-protein adducts upon injection of lipopolysaccharide into mouse cornea, a model of keratitis. We anticipated that docosahexaenoic acid-derived oxidatively truncated phospholipids containing reactive electrophilic 4-hydroxy-7-oxohept-5-enoates (HOHA) would convert the primary amino group of PEs into carboxyethylpyrrole phosphatidylethanolamine adducts (CEP-PEs). I detected a low level of CEP-PE in a bovine retinal lipid extract and quantified the generation of CEP-PE adduct and a CEP-modified lysophospholipid, lysoCEP-PE, upon UV light-promoted oxidation of the retinal lipid extract. Similar levels, about 1.2 ng/mL, of lysoCEP-PE were detected in plasma samples from a normal control and a patient with age-related macular degeneration (AMD). A reliable source of CEP-modified proteins was needed to provide: (1) reagents for immunoassays that measure levels of CEPs or anti-CEP autoantibodies as biomarkers for clinical prognosis of AMD, and (2) antigens to test the hypothesis that immune responses against CEP-protein adducts generated in the retina contribute to the pathogenesis of AMD, (3) for studies on the stimulation of angiogenesis by CEPs and its inhibition, and (4) for the production of CEP-PEs as standards for analyses of these potential markers of oxidative injury. An efficient, reliable synthesis of CEPs was developed that exploits a flourenylmethyl ester derivative of HOHA as a key reagent.