UNDERSTANDING IMMUNE CELL SIGNALING: EFFECT OF RETINOIDS ON ADAM SHEDDING

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 维生素A(视黄醇)及其类似物，维甲酸，对许多关键的生命过程是必不可少的，包括建立和维持免疫力。文献中充斥着关于维生素A对模型系统和生物体中免疫细胞的生长和功能的影响的研究。维甲酸通过调节白细胞的分化、增殖和运输，深刻影响免疫功能。然而，维甲酸控制这些过程并维持适当免疫的机制还知之甚少。类维甲酸，全反式维甲酸(t-RA)和9-顺式维甲酸(9-cis-RA)，通过核类维甲酸受体发挥作用，作为配体依赖的异源二聚体转录因子，改变去整合素和金属蛋白水解酶ADAMS的表达。ADAMS是一种人类蛋白质，参与一系列生物过程，并与免疫疾病状态有关，如类风湿性关节炎。ADAMS是一类新的整合素配体，通过对包括细胞因子、生长因子和维甲酸受体在内的分子进行蛋白水解性处理来执行胞外结构域脱落的关键功能。ADAMS的粘附性和蛋白分解功能之间的潜在相互作用仍然没有明确的定义，但项目负责人开发的模型假设，蛋白酶特异性是由去整合素域的整合素配体属性赋予的。ADAM的异常表达和/或ADAM整合素复合体的破坏被认为是最终导致不利于正常细胞功能的异常脱落事件。为了确定维甲酸在免疫细胞运输中的作用，该项目将研究维甲酸是否调节ADAMS在黏附和脱落方面的免疫功能。我们的初步结果表明，虽然一些细胞系对维甲酸有明显的反应，但其他类型的细胞对细胞黏附没有反应。显然，维甲酸的可用性和维甲酸受体配对调节了这些事件。

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.