FUNCTIONS OF INTRACELLULAR LIPID-BINDING PROTEINS

描述（由申请人提供）：膳食维生素A和长链脂肪酸（LCFA）产生信号分子，该信号分子通过其调节多个基因转录速率的能力来控制细胞过程。这些活性由称为核激素受体的配体诱导型转录因子介导。维生素A代谢物视黄酸（RA）通过激活核受体RAR和RXR来控制转录。介导LCFA及其衍生物转录活性的最佳表征受体是Tenned PPAR。除了核受体，RA和LCFA在细胞中与称为细胞内脂质结合蛋白（iLBP）的蛋白质家族成员相关联。RA与细胞视黄酸结合蛋白（CRABP-I和CRABP-II）结合，而LCFA与多种形式的脂肪酸结合蛋白（FABP）结合。近年来，核受体的作用机制已变得越来越清楚。相反，虽然通常认为iLBP在其配体的溶解和运输中起作用，但对不同iLBP同种型所起的具体作用仍然知之甚少。我们以前的研究导致CRABP-II的特定功能的鉴定。我们证明，CRABP-II（而不是CRABIP-I）调节RA的转录活性，通过直接与RAR的相互作用。我们最近进一步发现，一些FABPs可以调节PPARs的转录活性，表明除了CRABP-II之外，iLBPs也参与其配体的转录活性。该应用的目标是研究iLBP作为转录辅调节因子的作用。为此，我们建议描绘的机制，iLBPs调节配体依赖性活动的核受体，并澄清的功能后果的存在下，iLBPs的核受体在细胞中的生物活性。在2个特定目标下概述的研究中，我们建议澄清CRABP-II参与RAR的细胞活性，并探索FABP在调节PPARs转录活性中的作用。

DESCRIPTION (provided by applicant): Dietary vitamin A and long chain fatty acids (LCFA) give rise to signaling molecules that control cellular processes by virtue of their ability to modulate the rates of transcription of multiple genes. These activities are mediated by ligand inducible transcription factors known as nuclear hormone receptors. The vitamin A metabolite retinoic acid (RA) governs transcription by activating the nuclear receptors RAR and RXR. The best characterized receptors to mediate the transcriptional activities of LCFA and their derivatives are tenned PPAR. In addition to nuclear receptors, both RA and LCFA associate in cells with members of the family of proteins known as intracellular lipid-binding proteins (iLBP). RA binds to cellular retinoic acid binding proteins (CRABP-I and CRABP-II), while LCFA associate with multiple forms of fatty acid binding proteins (FABP). The mechanisms of action of nuclear receptors have become increasingly clear in recent years. In contrast, while it is generally believed that iLBPs function in solubilization and trafficking of their ligands, the specific roles served by the different iLBP isotypes remain poorly understood. Our previous studies led to the identification of a specific function for CRABP-II. We demonstrated that CRABP-II (but not CRABIP-I) modulates the transcriptional activity of RA through direct interactions with RAR. We recently found further that some FABPs can modulate the transcriptional activities of PPARs, demonstrating that iLBPs other than CRABP-II also participate in the transcriptional activities of their ligands. The goal of this application is to examine the roles of iLBPs as transcriptional co-regulators. To this end we propose to delineate the mechanisms by which iLBPs modulate the ligand-dependent activities of nuclear receptors, and to clarify the functional consequences of the presence of iLBPs for the biological activities of nuclear receptors in cells. In studies outlined under 2 specific aims we propose to clarify the involvement of CRABP-II in the cellular activities of RAR, and to explore the roles of FABPs in regulating the transcriptional activities of PPARs.