o Principal Investigator/Program Director (Last, first, middle): Davis, Ro,qer A. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED TIlE SPACE PROVIDED. Our hypothesis begins at the step in which Kupffer cells take up oxidized LDL. Since Kupffer cells express apo E and ATP cassette lipid transporters, we propose that proatherogenic lipids (i.e. oxidized phospholipids and oxysterols) taken up by Kupffer cells may be subsequently secreted into the hepatic sinusoids. The secretion of the proatherogenic lipids by Kupffer cells may be facilitated by forming lipoproteins in association with apo E which is in relatively high concentration within the hepatic sinusoids. The proatherogenic lipids may also be secreted by Kupffer cells via ABCA1 in association with apo A1, which is synthesized by the parenchymal cell. The resulting lipoprotein particles can be cleared by parenchymal cells via either the LDL receptor, the LDL receptor-like protein (LRP) or the SR-B1 receptor. Once taken up by parenchymal cells, we proposed there are three fates of the oxidized proatherogenic lipids: (1) excretion into bile, (2) catabolism and (3) secretion into plasma as a component of de novo synthesized lipoproteins. The manner in which these proatherogenic oxidized lipids are processed by the liver in part determines how much is available to reach the arterial wall and initiate atherogenesis. Our proposed studies will examine this hypothesis using transgenic mice and a method that selectively replaces Kupffer cells which were developed during the previous funding period. In addition to gaining new knowledge of lipid and lipoprotein metabolism, our research discoveries may enhance the potential therapeutic efficacy of our intervention of atherogenesis by gene transfer. During the next funding period, we will direct our efforts to achieving the following specific aims:
Specific aim 1 : to determine the role of the liver (parenchymal and Kupffer cells) in the production and inactivation of proatherogenic signaling molecules associated with oxidized LDL.
Specific Aim 2 : To use a novel method to selectively replace Kupffer cells with bone marrow derived cells in order to determine the molecular mechanisms through which liver parenchymal and Kupffer cells remove from plasma and metabolize proatherogenic lipids associated with oxidized LDL and these processes influence atherogenesis.
Specific Aim 3 : To determine the mechanism through which transgenic expression of CYP7A1 in LDL receptor -/- mice blocks diet-induced hyperlipidemia and how this affects atherogenesis. PERFORMANCE SITE ========================================Section End===========================================
| Bradshaw, Gary; Gutierrez, Alejandra; Miyake, Jon H et al. (2005) Facilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice. Proc Natl Acad Sci U S A 102:11029-34 |
