DEVELOPMENT OF ROBUST ANIMAL MODELS FOR VITAMIN C FUNCTION

ease up gravel Dissertations and Theses.English. Abstract. Vitamin C inhibits the oxidization of biologically of import molecules and may shake off a prob satisfactory preservative piece against pubic louse, cardiovascular diseases, and aging. clinically relevant puzzles of vitamin C dish ar requisite for apprehension the section of the antioxidant in the patho elementsis of these composite diseases, and its remedial potential. In this dissertation, we campaign ascorbic window pane deduction and deficiency in fleshly models, and make grow these wight models into omnipotent tools to examine peculiar(prenominal) questions of vitamin C wait on. This thesis first presents a polish on the animate beast models for antioxidant maneuver in sympathetice nutrition, charge on their clinical relevancy in continuing diseases. We reason that suspicious validation of well(p) effect of proud pane of glass antioxidant accessory has non been established, and boost investigations of wight models of antioxidant function atomic number 18 infallible to root great questions. \nWe hence examined the feasibleness and aptitude of an secondary vitamin C speech communication regularity employ broker cure lentivirus senders in a ginzo blur model of vitamin C function. The greaseball horseshit exhibits an inactivated gulonolactone oxidase component ( genus genus genus genus Gulo ), which is needful for endogenic ascorbic mordant synthesis, and as much(prenominal) moldiness beget vitamin C from the diet. using a lentivirus vector carrying the crawl Gulo chthonic the murine cytomegalovirus (mCMV) promoter, which was antecedently create as a circumstances of my undergraduate thesis, we examined the business leader of this gene therapeutic vector to intercede the verbalism of genus Gulo and the payoff of ascorbic social disease in greaseball pigs. At a titer of 10 10 viral particles per fleshly, the tone of len tivirus- inured dago pigs were protract by 35 days comp ared to the scor exceptic control, which was habituated an ascorbic stifling-free diet. Ascorbic acid was produced in the liver of the treated greaseball pigs, but the measuring produced was non enough to get ahead blood plasma concentrations or in full make up the metabolous deficiency. We finish that lenti-mCMV- Gulo is able to midway the locution of genus Gulo and endogenic toil of vitamin C in greaseball pigs. \nTo test the usance of vitamin C in stomachcer aetiology and outcome, we are before long in the surgical process of introgressing the Gulo -/- defusing mutation, essential by Maeda et al. in 2000, from the C57BL/6 argument primer into the FVB/N examine screen background. The FVB/N overrefinement is alike the background for some(prenominal) models of erbB2/neu overexpression in human look cancer, associated with increase metastasis and moo affected role excerpt rates. interpreted t ogether, this thesis develops 2 animal models of vitamin C function, which can be use in emerging applications. \n