Role of Progranulin in Mediating the Anti-Inflammatory Property of High-Density L

颗粒体蛋白前体在介导高密度 L 抗炎特性中的作用

• 批准号: 8397621
• 负责人: Andrew D. Nguyen
• 金额: $ 5.39万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-16 至 2015-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8397621
• 关键词: Age; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein A-I; Apolipoprotein E; Atherosclerosis; Binding; Blood; Cardiovascular Diseases; Cell Adhesion; Cell Adhesion Molecules; Collagen Arthritis; Disease; Endothelial Cells; Epidemiologic Studies; Frontotemporal Dementia; Genes; Glean; Growth Factor; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Immunoprecipitation; In Vitro; Incidence; Individual; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Knowledge; Link; Lipoproteins; Mass Spectrum Analysis; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; PGRN gene; Plasma; Play; Predisposition; Prevention; Progranulin; Property; Protein Binding; Proteins; Recombinants; Reporting; Role; Signal Transduction; TNF gene; Testing; Therapeutic; Tissues; Tumor Necrosis Factor Receptor; Vascular Cell Adhesion Molecule-1; base; density; in vivo; insight; macrophage; mouse model; protective effect; reverse cholesterol transport

DESCRIPTION (provided by applicant): High-density lipoprotein (HDL) is the smallest, most dense lipoprotein in plasma. Epidemiological studies from the past four decades have consistently found that HDL levels are inversely correlated with the incidence of cardiovascular disease. The protective effect of HDL is largely attributed to either its role in reverse cholesterl transport or its anti-inflammatory property. The anti-inflammatory property was described in 1995, based on HDL's ability to block TNF-a-induced expression of the cellular adhesion molecules VCAM-1 and ICAM-1 in endothelial cells. Although numerous studies have confirmed this finding, the mechanism underlying this anti-inflammatory property remains unknown. I propose to focus on a new candidate for mediating HDL's anti-inflammatory property. Progranulin is a secreted growth factor that is expressed in many tissues and circulates in the blood. The progranulin gene, GRN, is mutated in some cases of familial frontotemporal dementia. Progranulin has been reported to be associated with HDL. Interestingly, recent studies revealed that progranulin binds to TNF receptors, thereby establishing a link between progranulin and inflammation. Specifically, current models posit that progranulin antagonizes TNF signaling by competing with TNF-a for binding to TNF receptors. Further, mice lacking progranulin have enhanced susceptibility to collagen-induced arthritis, illustrating functional consequences involving inflammation. This raises the intriguing hypothesis that progranulin significantly contributes to the anti-inflammatory property of HDL. Completion of these studies is expected to provide important insights into the molecular basis underlying HDL's anti-inflammatory property. Knowledge gleaned from these studies will likely have therapeutic implications for the prevention and treatment of cardiovascular disease. Moreover, it would be directly relevant to individuals with mutations in the GRN gene, which is mutated in some cases of frontotemporal dementia. PUBLIC HEALTH RELEVANCE: In this proposal, I will test the role of progranulin in mediating the anti-inflammatory property of HDL cholesterol, which is one mechanism by which HDL is thought to protect against cardiovascular disease. I will also determine the functional importance of progranulin using a mouse model of atherosclerosis. Completion of these studies is expected to provide important insights about the molecular basis underlying HDL's anti-inflammatory property, which would likely have therapeutic implications for the prevention and treatment of cardiovascular disease.

描述（由申请人提供）：高密度脂蛋白（HDL）是血浆中最小、密度最大的脂蛋白。过去四十年的流行病学研究一致发现，HDL水平与心血管疾病的发病率呈负相关。HDL的保护作用主要归因于其在胆固醇逆向转运中的作用或其抗炎性质。1995年，基于HDL阻断TNF-α诱导的内皮细胞中细胞粘附分子VCAM-1和ICAM-1表达的能力，描述了抗炎特性。尽管许多研究已经证实了这一发现，但这种抗炎特性的机制仍然未知。我建议把重点放在一个新的候选人介导高密度脂蛋白的抗炎性质。颗粒蛋白原是一种分泌的生长因子，在许多组织中表达并在血液中循环。在家族性额颞叶痴呆的某些病例中，颗粒蛋白前体基因GRN发生突变。据报道，颗粒蛋白前体与HDL相关。有趣的是，最近的研究表明，颗粒蛋白前体与TNF受体结合，从而建立了颗粒蛋白前体与炎症之间的联系。具体地，目前的模型证实颗粒蛋白前体通过与TNF-α竞争结合TNF受体来拮抗TNF信号传导。此外，缺乏颗粒蛋白前体的小鼠对胶原诱导的关节炎的易感性增强，说明了涉及炎症的功能后果。这提出了一个有趣的假设，即颗粒蛋白前体显著有助于HDL的抗炎特性。这些研究的完成有望为HDL抗炎特性的分子基础提供重要的见解。从这些研究中收集的知识可能对预防和治疗心血管疾病具有治疗意义。此外，它与GRN基因突变的个体直接相关，GRN基因在某些额颞叶痴呆症病例中发生突变。 公共卫生关系：在这个提议中，我将测试颗粒蛋白前体在介导HDL胆固醇的抗炎特性中的作用，这是HDL被认为可以预防心血管疾病的一种机制。我还将使用动脉粥样硬化小鼠模型确定颗粒蛋白前体的功能重要性。这些研究的完成有望为HDL抗炎特性的分子基础提供重要的见解，这可能对预防和治疗心血管疾病具有治疗意义。