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Oxidized Lipids in Cardiovascular Disease

心血管疾病中的氧化脂质

基本信息

批准号：
7228616
负责人：
Nalini Santanam
金额：
$ 33.19万
依托单位：
MARSHALL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2012-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Oxidized free fatty acids (Ox-FFA) have profound effect on cells. Most of these effects are deleterious and pro-atherogenic. Surprisingly, they also have beneficial effects such as induction of catalase. These could be some of the "hidden" effects of PPAR signaling as some of the PPAR ligands are known activators of catalase, a peroxisomal enzyme. On the other hand, the activation of antioxidant enzymes could also represent cellular defense to an oxidative stress. Understanding the basis of these effects would help us to determine conditions under which the anti-atherogenic effects would prevail over their pro- atherogenic effects. Ox-FFA are poorly transported into cells and poorly utilized for esterification reactions. Thus, small amounts of Ox-FFA that enter the cell might be more readily available for intracellular signaling pathways, i.e. as ligands for PPARs, or destined for degradation pathways. The overall hypothesis of the proposal is, "Cells regulate the uptake and presence of Ox-FFA. The small amounts of Ox-FFA that enter the cell could act as PPAR ligands. Their degradation in peroxisomes would generate H202 thus accounting for their toxicity. The induction of antioxidant enzymes by Ox-FFA might be in response to the generation of H202 or via PPARs". AIM 1: To determine why the uptake of Ox-FFA is poor as compared to that of unoxidized fatty acids. We propose that the increased polarity of Ox-FFA and/or a saturable membrane protein or domain might contribute to the poor uptake of Ox-FFA. Using chemical modifications and membrane alterations, we will determine the changes in the uptake of Ox-FFA. We will also determine the intracellular fate of Ox-FFA. AIM 2: To determine the potential degradation of Ox-FFA in the peroxisomes generating H202. We will determine the intracellular degradation of Ox-FFA such as generation of H202 and other polar products as a measure of peroxisomal oxidation. Using acyl CoA oxidase knock out mice, we will determine whether the effects of Ox-FFA could be attributed to its ability to affect peroxisomal metabolism. We will also demonstrate whether Ox-FFA, analogous to the fibrates would induce peroxisomes in animal and cell culture models. AIM 3: To determine whether cellular PPAR and non-PPAR mediated cellular responses to Ox-FFA. Using biochemical and molecular approaches, we will determine and delineate PPAR dependent and independent effects of Ox-FFA.

描述（由申请人提供）：氧化游离脂肪酸（Ox-FFA）对细胞有深远的影响。大多数这些影响是有害的和促动脉粥样硬化的。令人惊讶的是，它们还具有有益的效果，例如诱导过氧化氢酶。这些可能是PPAR信号传导的一些“隐藏”效应，因为一些PPAR配体是过氧化氢酶（过氧化物酶体酶）的已知激活剂。另一方面，抗氧化酶的激活也可以代表细胞对氧化应激的防御。了解这些作用的基础将有助于我们确定抗动脉粥样硬化作用优于其促动脉粥样硬化作用的条件。Ox-FFA很难转运到细胞中，并且很难用于酯化反应。因此，进入细胞的少量Ox-FFA可能更容易用于细胞内信号传导途径，即作为PPARs的配体，或用于降解途径。该提案的总体假设是，“细胞调节Ox-FFA的摄取和存在。进入细胞的少量Ox-FFA可以作为PPAR配体。它们在过氧化物酶体中的降解会产生H2 O2，从而解释了它们的毒性。Ox-FFA对抗氧化酶的诱导可能响应于H2 O2的产生或经由PPARs。目的1：确定与未氧化的脂肪酸相比，Ox-FFA的摄取较差的原因。我们建议，增加极性的Ox-FFA和/或饱和的膜蛋白或结构域可能有助于Ox-FFA的吸收不良。使用化学修饰和膜改变，我们将确定Ox-FFA摄取的变化。我们还将确定Ox-FFA的细胞内命运。目的2：确定Ox-FFA在产生H2 O2的过氧化物酶体中的潜在降解。我们将确定Ox-FFA的细胞内降解，例如H2 O2和其他极性产物的产生，作为过氧化物酶体氧化的量度。使用酰基辅酶A氧化酶敲除小鼠，我们将确定Ox-FFA的作用是否可以归因于其影响过氧化物酶体代谢的能力。我们还将证明Ox-FFA是否类似于贝特类药物，在动物和细胞培养模型中诱导过氧化物酶体。目的3：探讨细胞型和非细胞型过氧化物酶体增殖物激活受体（PPAR）是否介导氧化型荧光素酶（Ox-FFA）的细胞反应。利用生物化学和分子生物学的方法，我们将确定和描绘过氧化物酶体增殖物激活受体的依赖性和独立的Ox-FFA的影响。