The liver and intestine secrete apolipoprotein (apo-)B-containing lipoproteins, which transport lipid-soluble substances, such as cholesterol, triacylglycerols, and fat-soluble vitamins (e.g., vitamin E), through the circulation. Through studies involving apo-B knockout (Apob-/- ) mice, we have shown that the mouse yolk sac project is to characterize further the synthesis and secretion of lipoproteins by the yolk sac during development, focusing on the role of alpha-tocopherol transfer protein (alpha-TTP), a cytosolic protein hypothesized to be involved in apo-B containing lipoprotein assembly in liver. In hepatocytes, alpha-TTP is thought to enrich lipoproteins in one form of vitamin E, RRR-alpha tocopherol, and thus alpha-TTP is thought to enrich lipoproteins in one form of vitamin E, RRR-alpha-tocopherol, and thus alpha-TTP is a chief determinant of plasma vitamin E levels.
Aim 1 is to characterize further the mouse yolk sac as a lipoprotein-secreting tissue by 1) determining the expression pattern of alpha-TTP and other molecules (e.g., apo-B and the microsomal triglyceride transfer protein) involved in lipoprotein assembly and 2) analyzing the ultrastructure of yolk sac visceral endoderm cells during different stages of development. We will also use Apob-/- embryonic stem cells and chimeric mice to search for other lipoprotein -secreting organs of physiologic significance (e.g., heart, kidney, testis).
Aim 2 is to generate alpha-TTP knockout (Ttp-/-) mice to characterize their phenotype with regard to vitamin E metabolism and embryonic development. Because mouse alpha-TTP deficiency may result in embryonic lethality, our plans will include the use of LoxP/Cre recombinase methodology to develop a liver-specific alpha-TTP knockout, if needed to generate a viable model of alpha-TTP deficiency.
Aim 3 is to determine whether alpha-TTP and vitamin E deficiencies in mice result in the increased development of atherosclerosis by analyzing lesion development in alpha-TTP-deficient and control mice fed an atherogenic diet. We will also characterize the plasma lipoproteins in alpha-TTP deficient mice with respect to vitamin E levels and their susceptibility to oxidation. An alpha-TTP-deficient mouse model will provide an animal model for human ataxia and isolated vitamin E deficiency syndrome and will provide a valuable genetically induced model of vitamin E deficiency in rodents.
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