Identification of endogenous ligands for the Retinoid-related Orphan Receptor gamma

类维生素A相关孤儿受体γ内源配体的鉴定

• 批准号: BB/L001942/1
• 负责人: Yuqin Wang
• 金额: $ 48.7万
• 依托单位: Swansea University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL001942%2F1
• 关键词: Identification; endogenous; ligands; Retinoid; related

In the body's defence against invading pathogens, T cells are essential to protect the body from infection. However, uncontrolled and persistent T cell responses can drive the onset of autoimmunity i.e. the immune system reacts against self tissue. TH17 cells, a specific subset of T cells, have an important role in host defence against certain bacteria and fungi and importantly, are potent inducers of autoimmunity and are implicated in autoimmunity diseases including rheumatoid arthritis and multiple sclerosis. The development of TH17 cells is dependent on RORgammat, a ligand activated transcription factor. For activation, RORgammat requires the binding of a cholesterol derived ligand to initiate the transcription of targeted genes. However, the endogenous ligands of RORgammat which promote TH17 generation and maintains its function are still unknown. Therefore, the goal of this study is to identify endogenous ligands of RORgammat, find out how they regulate TH17 cell development and elucidate the process of their formation and deactivation. These findings will reveal new drug targets and a rationale for therapeutic intervention of autoimmune diseases.

在身体抵御入侵病原体的防御中，T细胞对于保护身体免受感染至关重要。然而，不受控制的和持续的T细胞反应可以驱动自身免疫的发作，即免疫系统对自身组织作出反应。TH17细胞是T细胞的一个特定亚群，在宿主防御某些细菌和真菌方面具有重要作用，重要的是，它是自身免疫的有效诱导剂，并与包括类风湿性关节炎和多发性硬化症在内的自身免疫疾病有关。TH17细胞的发育依赖于ROR γ mat，一种配体激活的转录因子。为了激活，ROR γ需要结合胆固醇衍生的配体以启动靶基因的转录。然而，促进TH17生成并维持其功能的ROR γ mat的内源性配体仍然未知。因此，本研究的目的是鉴定ROR γ mat的内源性配体，找出它们如何调节TH17细胞的发育，并阐明其形成和失活的过程。这些发现将揭示新的药物靶点和自身免疫性疾病治疗干预的基本原理。

项目成果

Reduced Plasma Levels of 25-Hydroxycholesterol and Increased Cerebrospinal Fluid Levels of Bile Acid Precursors in Multiple Sclerosis Patients.

• DOI: 10.1007/s12035-016-0281-9
• 发表时间: 2017-12
• 期刊: Molecular neurobiology
• 影响因子: 5.1
• 作者: Crick PJ;Griffiths WJ;Zhang J;Beibel M;Abdel-Khalik J;Kuhle J;Sailer AW;Wang Y
• 通讯作者: Wang Y

Revised sample preparation for the analysis of oxysterols by enzyme-assisted derivatisation for sterol analysis (EADSA).

• DOI: 10.1007/s00216-015-8609-2
• 发表时间: 2015-07
• 期刊: ANALYTICAL AND BIOANALYTICAL CHEMISTRY
• 影响因子: 4.3
• 作者: Crick, Peter J.;Bentley, T. William;Wang, Yuqin;Griffiths, William J.
• 通讯作者: Griffiths, William J.

Defective cholesterol metabolism in amyotrophic lateral sclerosis.

• DOI: 10.1194/jlr.p071639
• 发表时间: 2017-01
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Abdel-Khalik J;Yutuc E;Crick PJ;Gustafsson JÅ;Warner M;Roman G;Talbot K;Gray E;Griffiths WJ;Turner MR;Wang Y
• 通讯作者: Wang Y

Developing an Enzyme-Assisted Derivatization Method for Analysis of C27 Bile Alcohols and Acids by Electrospray Ionization-Mass Spectrometry.

开发一种酶辅助衍生化方法，用于通过电喷雾电离质谱法分析 C27 胆汁醇和酸。

• DOI: 10.3390/molecules24030597
• 发表时间: 2019
• 期刊: Molecules (Basel, Switzerland)
• 作者: Abdel-Khalik J

Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.

• DOI: 10.1016/j.jsbmb.2020.105794
• 发表时间: 2021-03
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Abdel-Khalik J;Hearn T;Dickson AL;Crick PJ;Yutuc E;Austin-Muttitt K;Bigger BW;Morris AA;Shackleton CH;Clayton PT;Iida T;Sircar R;Rohatgi R;Marschall HU;Sjövall J;Björkhem I;Mullins JGL;Griffiths WJ;Wang Y
• 通讯作者: Wang Y