UNDERSTANDING IMMUNE CELL SIGNALING: EFFECT OF RETINOIDS ON ADAM SHEDDING

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 维生素A（视黄醇）及其类似物，类维生素A，是许多关键生命过程所必需的，包括建立和维持免疫力。文献中充满了关于维生素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。类维生素A通过调节白细胞的分化、增殖和运输而深刻地影响免疫功能。然而，维甲酸控制这些过程和维持适当免疫力的机制知之甚少。类视色素，全反式视黄酸（t-RA）和9-顺式视黄酸（9-cis-RA），通过核视色素受体起作用，并作为配体依赖性异二聚体转录因子起作用，其改变亚当斯（解整合素和金属蛋白酶）的表达。亚当斯是参与一系列生物过程的人类蛋白质，并与免疫疾病状态有关，如类风湿性关节炎。亚当斯是一类新的整联蛋白配体，其被充分表征为通过分子（包括细胞因子、生长因子和有趣的类视色素受体）的蛋白水解加工来执行胞外域脱落的关键功能。亚当斯的粘附和蛋白水解功能之间的潜在相互作用仍然不清楚，但项目负责人开发的模型表明，蛋白酶特异性是由去整合素结构域的整合素配体特性赋予的。异常ADAM表达和/或ADAM破坏整联蛋白复合物被认为最终导致对正常细胞功能有害的异常脱落事件。为了确定类维生素A在免疫细胞运输中的作用，本项目将研究类维生素A是否调节亚当斯在粘附和脱落方面的免疫功能。我们的初步结果已经确定，虽然一些细胞系是明确的类维生素A反应，其他类型的细胞是无反应的细胞粘附。显然，类维生素A的可用性和类维生素A受体配对介导这些事件。

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.