UNDERSTANDING IMMUNE CELL SIGNALING: EFFECT OF RETINOIDS ON ADAM SHEDDING

了解免疫细胞信号传导：类维生素A对亚当脱落的影响

• 批准号: 8359814
• 负责人: Melissa Hernandez
• 金额: $ 9.9万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359814
• 关键词: Adhesions; Adhesives; Affect; All-Trans-Retinol; Animal Model; Arkansas; Biological Models; Biological Process; Biomedical Research; Cell Adhesion; Cell Lineage; Cell physiology; Cells; Complex; Disintegrin Domain; Disintegrins; Event; Funding; Grant; Growth; Growth Factor; Human; Immune; Immune System Diseases; Immunity; Integrins; Leukocyte Trafficking; Life; Ligands; Literature; Maintenance; Mediating; Metalloproteases; Modeling; National Center for Research Resources; Normal Cell; Nuclear; Peptide Hydrolases; Principal Investigator; Process; Property; Proteins; Proteolytic Processing; Research; Research Infrastructure; Resources; Retinoid Receptor; Retinoids; Rheumatoid Arthritis; Role; Signal Transduction; Source; Specificity; Tretinoin; United States National Institutes of Health; Vitamin A; alitretinoin; analog; cell type; cost; cytokine; immune function; novel; receptor function; trafficking; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Vitamin A (retinol) and its analogs, retinoids, are essential for many critical life processes, including establishment and maintenance of immunity. The literature is replete with studies on the influence of vitamin A on the growth and function of immune cells in model systems and organisms. Retinoids profoundly affect immune function by regulating the differentiation, proliferation, and trafficking of leukocytes. However, the mechanism by which retinoids govern these processes and maintain proper immunity is poorly understood. Retinoids, all-trans-retinoic acid (t-RA) and 9-cis-retinoic acid (9-cis-RA), act through nuclear retinoid receptors and function as ligand-dependent heterodimer transcription factors that alter the expression of ADAMs, a disintegrin and metalloproteases. ADAMs are human proteins involved in a spectrum of biological processes and are implicated in immune disease states, such as rheumatoid arthritis. ADAMs are a novel class of integrin ligand that is well characterized for executing the critical function of ectodomain shedding via proteolytic processing of molecules, including cytokines, growth factors, and, interestingly, retinoid receptors. The potential interplay between the adhesive and proteolytic functions of ADAMs remains poorly defined, but models developed by the Project Leader posit that protease specificity is bestowed by the integrin ligand properties of the disintegrin domain. Abnormal ADAM expression and/or disruption of ADAMintegrin complexes are believed to culminate in aberrant shedding events detrimental to normal cell function. To define the role of retinoids in immune-cell trafficking, this project will examine whether retinoids modulate immune functions of ADAMs with respect to adhesion and shedding. Our preliminary results have established that while some cell lineages are clearly retinoid-responsive, other cell types are nonresponsive with respect to cellular adhesion. Clearly, retinoid availability and retinoid receptor pairings mediated these events.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 维生素 A（视黄醇）及其类似物、类视黄醇对于许多关键的生命过程至关重要，包括建立和维持免疫力。文献中有大量关于维生素 A 对模型系统和生物体中免疫细胞生长和功能影响的研究。类维生素A通过调节白细胞的分化、增殖和运输来深刻影响免疫功能。然而，人们对类维生素A控制这些过程并维持适当免疫力的机制知之甚少。类视黄酸、全反式视黄酸 (t-RA) 和 9-顺式视黄酸 (9-cis-RA) 通过核视黄酸受体发挥作用，并作为配体依赖性异二聚体转录因子，改变 ADAM 的表达。解整合素和金属蛋白酶。 ADAM 是参与一系列生物过程的人类蛋白质，与类风湿性关节炎等免疫疾病状态有关。 ADAM 是一类新型整联蛋白配体，其特征在于通过分子的蛋白水解加工执行胞外域脱落的关键功能，这些分子包括细胞因子、生长因子以及有趣的视黄醇受体。 ADAM 的粘附功能和蛋白水解功能之间的潜在相互作用仍不清楚，但项目负责人开发的模型认为，蛋白酶特异性是由解整合素结构域的整合素配体特性赋予的。据信 ADAM 表达异常和/或 ADAM 整联蛋白复合物破坏最终会导致异常脱落事件，损害正常细胞功能。为了确定类维生素A在免疫细胞运输中的作用，该项目将研究类维生素A是否调节ADAM在粘附和脱落方面的免疫功能。我们的初步结果表明，虽然某些细胞谱系具有明显的类视黄醇反应性，但其他细胞类型对细胞粘附没有反应。显然，类维生素A的可用性和类维生素A受体配对介导了这些事件。