Regulation of Lipid Metabolism and Inflammation by the Orphan Nuclear Receptors

我们实验室的一个长期目标是了解脂质激活的转录因子在 人类疾病中代谢和炎症基因表达的协调。已完成的工作 目前的授权期描绘了LXR和NR4A核受体在控制 胆固醇和葡萄糖代谢，也揭示了这些因素在免疫中意想不到的作用 回应。在下一个资助期，我们建议延长先前的工作，以解决LXR在 代谢-免疫串扰在三个层面上：先天免疫反应、获得性免疫功能和 先天免疫系统和后天免疫系统之间的串扰。我们进一步建议在我们的发现的基础上 NR4A核受体在炎症和炎症的转录调控中的重要性 新陈代谢。总的来说，这些研究有望促进我们对分子的理解。 在生理和疾病中整合代谢和炎症过程的途径。我们的首要目标是 验证IRF3信号代谢激活调节LXR功能和胆固醇的假说 新陈代谢。我们将探索脂质介质对IRF3信号的影响，并测试IRF3- LXR对动脉粥样硬化发展的串扰作用。我们的第二个目标是检验脂类依赖的假设 LXR信号是淋巴细胞功能的生理调节器。我们将确定机制 胆固醇代谢和LXR信号调节适应性免疫反应 淋巴细胞依赖性炎症性疾病的发展。我们还将定义 合成LXR激动剂的免疫调节作用。我们的第三个目标是定义 巨噬细胞NR4A受体在炎症和动脉粥样硬化发展中的作用 功能性小鼠模型。我们将测试NR4A受体参与的串扰 炎症和代谢信号，并确定潜在的这种串扰的机制。完成 这些目标有望为新陈代谢的基本机制和 这可能会为心血管疾病的治疗干预提供新的机会。

A long-term goal of our laboratory is to understand the role that lipid-activated transcription factors play in the coordination of metabolic and inflammatory gene expression in human disease. Work accomplished in the current grant period delineated new functions for LXR and NR4A nuclear receptors in the control of cholesterol and glucose metabolism and also revealed unexpected roles for these factors in immune responses. In the next funding period we propose to extend prior work to address the function of LXR in metabolic-immune crosstalk on three levels: innate immune responses, acquired immune functions, and crosstalk between the innate and acquired immune systems. We further propose to build upon our discovery of the importance of NR4A nuclear receptors in the transcriptional control of both inflammation and metabolism. Collectively, these studies are expected to advance our understanding of the molecular pathways that integrate metabolic and inflammatory processes in physiology and disease. Our first aim is to test the hypothesis that metabolic activation of IRF3 signaling regulates LXR function and cholesterol metabolism. We will explore the impact of lipid mediators on IRF3 signaling and test the influence of IRF3- LXR crosstalk on the development of atherosclerosis. Our second aim is to test the hypothesis that lipiddependent LXR signaling is a physiologic modulator of lymphocyte function. We will determine mechanisms whereby cholesterol metabolism and LXR signaling regulate adaptive immune responses and the development of lymphocyte-dependent inflammatory diseases. We will also define the mechanistic basis for the immunomodulatory effects of synthetic LXR agonists. Our third aim is to define the impact of macrophage NR4A receptors on inflammation and the development of atherosclerosis using gain- and lossof- fucntion mouse models. We will test the involvement of NR4A receptors in crosstalk between inflammatory and metabolic signaling and determine the mechanisms underlying such crosstalk. Completion of these aims is expected to bring new insight into fundamental mechanisms underlying metabolism and inflammation and may suggest new opportunities for therapeutic intervention in cardiovascular disease.