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Role of Fatty Acid Binding Proteins in Lipid Signaling

脂肪酸结合蛋白在脂质信号转导中的作用

基本信息

批准号：
6842223
负责人：
Liza Makowski-Hayes
金额：
$ 4.83万
依托单位：
DUKE 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：
2004-01-01 至 2005-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6842223
关键词：
atherosclerosis biological signal transduction cholesterol fatty acid binding protein laboratory mouse lipid metabolism lipids macrophage peroxisome proliferator activated receptor postdoctoral investigator protein structure function tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): It is likely that a FA binding protein (FABP) will regulate FA-sensitive intracellular signaling pathways involved in the pathogenesis of Metabolic Syndrome. We have reported two FABP-deficient mouse models, aP2-/- and mal1-/-, that are protected from developing obesity-induced insulin resistance and atherosclerosis to varying degrees, aP2 and mal1 are highly expressed in the macrophage, a cell important in the formation of atheroscterosic lesions. In the absence of aP2, macrophages have alterations in FA and cholesterol metabolism. The hypothesis is that FABPs will modify macrophage lipid biology. This proposal aims to further characterize the direct mechanism of FABP action in macrophage biology. First, lipid metabolism will be investigated in established single (aP2 or mal1) and double (aP2/mal1) -/- macrophage cell lines. Second, the cholesterol metabolic pathway will be studied in these cell lines. Third, inhibitors to proteins central to the cholesterol efflux pathway, namely PPARgamma, will be used in wildtype and FABP null macrophage cell lines to demonstrate at which point in the pathway FABPs are acting. Ultimately, FABP-deficient mice will be crossed into mice deficient for one of these candidate proteins to examine primary macrophage biology, and the formation of atherosclerosis.

描述（由申请人提供）：FA结合蛋白（FABP）可能会调节参与代谢综合征发病机制的FA敏感的细胞内信号传导途径。我们报道了两种FABP缺陷小鼠模型，aP2-/-和mal1-/-，它们在不同程度上免受肥胖引起的胰岛素抵抗和动脉粥样硬化的影响，aP2和mal1在巨噬细胞中高度表达，巨噬细胞是动脉粥样硬化病变形成的重要细胞。在缺乏 aP2 的情况下，巨噬细胞的 FA 和胆固醇代谢会发生改变。假设 FABP 会改变巨噬细胞脂质生物学。该提案旨在进一步表征 FABP 在巨噬细胞生物学中作用的直接机制。首先，将在已建立的单（aP2 或 mal1）和双（aP2/mal1）-/- 巨噬细胞系中研究脂质代谢。其次，将研究这些细胞系中的胆固醇代谢途径。第三，胆固醇流出途径核心蛋白（即 PPARgamma）的抑制剂将用于野生型和 FABP 无效巨噬细胞系，以证明 FABP 在途径中的哪个点发挥作用。最终，将缺乏 FABP 的小鼠与缺乏其中一种候选蛋白的小鼠杂交，以检查原代巨噬细胞生物学和动脉粥样硬化的形成。