LXRA GENE POLYMORPHISMS AND RESPONSE TO FENOFIBRATE

LXRA 基因多态性和对非诺贝特的反应

• 批准号: 7950756
• 负责人: MARIAN C. LIMACHER
• 金额: $ 1.5万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7950756
• 关键词: Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Attenuated; C-reactive protein; Cardiovascular Diseases; Clinic; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Drug Delivery Systems; Exhibits; Fenofibrate; Fibrates; Funding; Genes; Genetic Polymorphism; Grant; High Density Lipoproteins; Homeostasis; Human body; Inflammation; Inflammation Mediators; Institution; Link; Lipids; Liver; Low-Density Lipoproteins; Nuclear Receptors; Pathogenesis; Pharmaceutical Preparations; Pharmacological Treatment; Prevention; Process; Property; Research; Research Personnel; Resources; Risk Factors; Source; Triglycerides; United States National Institutes of Health; inflammatory marker; insight; killings; lipoprotein cholesterol; receptor; response; reverse cholesterol transport; sensor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cardiovascular disease-CVD kills almost 17 million people internationally every year. Evidence indicates that abnormal lipoprotein, cholesterol, levels and inflammation are linked to CVD pathogenesis. Elevated low-density lipoprotein-LDL, triglycerides, and inflammatory markers, and low high-density lipoprotein-HDL levels are risk factors for CVD development and progression. Current pharmacological treatments for prevention include drugs aimed at restoring lipid homeostasis, which also possess ancillary anti-inflammatory properties such as PPAR-a agonists, e.g., fenofibrate. Liver X receptor a-LXRA is a nuclear receptor known to function as a lipid sensor in the human body and serves as a regulator of lipid homeostasis and suppressor of inflammation. The fibrates are known to modulate reverse cholesterol transport and attenuate inflammation via the LXRA receptor. There is a considerable amount of variability in response to these drugs, and contributing factors to this variability are not well understood. Since LXRA is a drug target for the lipid-modulating effects of fibrates, variability in the gene that encodes LXRA, NR1H3, may be an important determinant of the drug response. Fibrates have also been noted to exhibit so-called pleiotropic effects which include reductions in the prototypical inflammatory mediator of atherosclerosis, C-reactive protein-CRP. It is unknown whether genetic polymorphisms impact these pharmacological effects of fibrates. We propose to investigate whether common NR1H3 gene polymorphisms are associated with either the lipid-modifying or anti-inflammatory effect of fibrates. This approach may add to the understanding of atherosclerotic disease as a systemic process and offer insights into variability in drug response to the biologic and clinic effects of fibrates.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 每年，心血管疾病-CVD在国际上杀死近1700万人。 证据表明，异常的脂蛋白，胆固醇，水平和炎症与CVD发病机理有关。 低密度脂蛋白-LDL，甘油三酸酯和炎症标志物以及低密度脂蛋白-HDL水平是CVD发展和进展的危险因素。 当前的预防药理治疗方法包括旨在恢复脂质稳态的药物，该药物还具有辅助抗炎特性，例如PPAR-A激动剂，例如fenofibrate。 肝脏X受体A-LXRA是一种核受体，被称为人体中的脂质传感器，并作为脂质稳态和炎症抑制剂的调节剂。 已知这些纤维可调节反向胆固醇的转运，并通过LXRA受体减轻炎症。 对这些药物的响应有很大的可变性，并且对这种变异性的贡献尚不清楚。 由于LXRA是纤维化脂肪调节作用的药物靶标，因此编码LXRA，NR1H3的基因的变异性可能是药物反应的重要决定因素。 还注意到纤维化物表现出所谓的多效性作用，包括减少动脉粥样硬化的典型炎症介质C反应性蛋白质-CRP。 尚不清楚遗传多态性是否影响纤维化的这些药理作用。 我们建议研究常见的NR1H3基因多态性是否与纤维化的脂质修饰或抗炎作用有关。 这种方法可能会增加对动脉粥样硬化疾病的理解，并提供对药物反应对纤维化生物和临床效应的可变性的见解。