内源性和外源性肝脏X受体激动剂在视网膜炎症中的相反作用及其机制的研究

Inflammation is a pathological process shared by many retinal diseases. The relationship between the lipid homeostasis and inflammation is becoming the front line of medical research. Our lab and others have found that activation of liver X receptor (LXR), which is a major regulator of cholesterol metabolism, with a synthesized ligand inhibits retinal inflammation and is promising to become a novel class of drug for treating retinal inflammation. Nevertheless, limited reports suggest endogenerous LXR exaggerate retinal inflammation. We hypothesis that opposite functions of the exogenerous and endogenerous LXR activators on retinal inflammation are mediated by different mechanisms. Aims: 1. To confirm 7-KC induces retinal cell inflammation via activating LXRs and their target genes in vitro; 2. To confirm the opposite functions of the exogenerous and endogenerous LXR activators in LPS mediated inflammation in vitro and in vivo. 3. To confirm the opposite functions of the exogenerous and endogenerous LXR activators in amyloid Beta induced retinal inflammation in vitro and in vivo. 4. To explore the underlying mechanisms by genomics and proteomics with next generation sequencing techniques. 5. To confirm the mechanisms of the opposite functions by molecular biology methods. The proposed study will provide not only in-depth knowledge towards understanding the relationship between lipid homeostasis and retinal inflammation, but also critical safety information for developing novel anti-inflammation drugs targeting on LXRs.

炎症是许多视网膜疾病的共同病理特征。脂质代谢平衡与炎症的关系正成为新的研究热点。我们及其他实验室发现，脂质代谢关键受体肝脏X受体（LXR）的外源性激动剂可抑制视网膜炎症并可能成为治疗视网膜炎症反应的一类新药。然而有报道提示内源性LXR激动剂7-酮基胆固醇（7KC）却能加重视网膜炎症反应。我们假设外源性和内源性LXR激动剂通过不同机制对炎症产生影响。目的：1. 体外证实7-KC可激活LXR及其靶基因ABCA1、ABCG1并引起视网膜细胞炎症反应；2. 体内和体外证实内外源性LXR激动剂对LPS诱导视网膜细胞炎症反应有相反作用；3. 体内和体外证实内外源性LXR激动剂对淀粉样蛋白引起的炎症反应有相反作用；4. 基因和蛋白质组学探讨引起相反作用的机制；5. 分子生物学验证引起相反作用的机制。本研究将深入探讨脂质代谢与视网膜炎症的联系，为研发通过调控LXR干预视网膜炎症的新型药物提供安全性的依据。

炎症是许多视网膜疾病的共同病理特征。脂质代谢平衡与炎症的关系正成为新的研究热点。我们通过研究发现，脂质代谢关键受体肝脏X受体（LXR）的外源性激动剂可抑制视网膜炎症并可能成为治疗视网膜炎症反应的一类新药。我们通过体内实验和体外实验证实了外源性和内源性LXR激动剂通过不同机制对炎症产生不同的影响。主要研究内容包括：1. 体外证实7-KC可激活LXR及其靶基因ABCA1、ABCG1并引起视网膜细胞炎症反应；2. 体内和体外证实内外源性LXR激动剂对LPS诱导视网膜细胞炎症反应有相反作用；3. 体内和体外证实内外源性LXR激动剂对淀粉样蛋白引起的炎症反应有相反作用；4. 基因和蛋白质组学探讨引起相反作用的分子机制；5. 分子生物学验证引起相反作用的机制。本研究深入探讨了脂质代谢与视网膜炎症的联系，为研发通过调控LXR干预视网膜炎症的新型药物提供了安全性依据。