Coxsackie and adenovirus receptor (CAR): functions of a novel adhesion molecule

柯萨奇和腺病毒受体（CAR）：新型粘附分子的功能

• 批准号: 386391-2012
• 负责人: Nalbantoglu, Josephine
• 金额: $ 2.48万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=572947
• 关键词: Coxsackie; adenovirus; receptor; CAR; functions

The Coxsackie and adenovirus receptor (CAR) is a novel member of the immunoglobulin superfamily of adhesion molecules. As its name implies, it was first identified as the high affinity receptor for adenovirus type 5, the most commonly used adenoviral vector for gene transfer. My laboratory's interest in CAR stems from our routine use adenovirus (Ad) vectors for gene transfer to muscle, nervous system and tumour cells. Thus, we have been interested in determining the expression pattern of CAR and means of modulating its expression, as well as examining its function in these tissues. CAR expression is regulated developmentally and in a tissue-specific manner. Highest levels of CAR expression are observed in prenatal and neonatal tissues. This pattern of expression suggests CAR could play a role in the growth, migration or differentiation of embryonic or neonatal tissues. Such a role for CAR is further supported by the observation of loss of CAR expression in several types of cancer. Our long term objective is to understand how an adhesion molecule such as CAR transmits extracellular cues into intracellular signals. We have concentrated on two biological systems, tumour cells and neurons. In both cell types, CAR plays crucial roles in cell migration. In tumour cells, CAR expression leads to inhibition of migration and invasion while in neurons, CAR expression promotes process extension (neurite outgrowth). We have shown CAR can undergo metalloprotease-mediated shedding of its extracellular domain, followed by cleavage through the gamma-secretase complex to produce an intracellular cytoplasmic fragment, thus generating potentially important signalling molecules. CAR expression is highest in the developing nervous system, making primary neuronal cultures and mouse embryonic nervous system development the ideal experimental models to study CAR function. Our specific objectives are to:1) determine the functional relevance of the proteolytic processing of CAR; 2) determine whether CAR's intracellular cytoplasmic domain plays a signaling role; 3) study the function of CAR in the developing nervous system.

柯萨奇腺病毒受体 (CAR) 是粘附分子免疫球蛋白超家族的新成员。顾名思义，它首先被鉴定为 5 型腺病毒的高亲和力受体，5 型腺病毒是最常用的基因转移腺病毒载体。我的实验室对 CAR 的兴趣源于我们常规使用腺病毒 (Ad) 载体将基因转移到肌肉、神经系统和肿瘤细胞。因此，我们一直对确定 CAR 的表达模式和调节其表达的方法以及检查其在这些组织中的功能感兴趣。 CAR 表达以组织特异性方式在发育过程中受到调节。在产前和新生儿组织中观察到最高水平的 CAR 表达。这种表达模式表明 CAR 可能在胚胎或新生儿组织的生长、迁移或分化中发挥作用。在几种类型的癌症中观察到 CAR 表达缺失，进一步支持了 CAR 的这种作用。 我们的长期目标是了解 CAR 等粘附分子如何将细胞外信号传递为细胞内信号。我们专注于两个生物系统：肿瘤细胞和神经元。在这两种细胞类型中，CAR 在细胞迁移中发挥着至关重要的作用。在肿瘤细胞中，CAR 表达会抑制迁移和侵袭，而在神经元中，CAR 表达会促进过程延伸（神经突生长）。我们已经证明，CAR 可以经历金属蛋白酶介导的胞外结构域脱落，然后通过 γ-分泌酶复合物裂解，产生胞内胞质片段，从而产生潜在的重要信号分子。 CAR 表达在发育中的神经系统中最高，这使得原代神经元培养物和小鼠胚胎神经系统发育成为研究 CAR 功能的理想实验模型。我们的具体目标是：1) 确定 CAR 蛋白水解加工的功能相关性； 2）确定CAR的胞内胞质结构域是否发挥信号传导作用； 3）研究CAR在神经系统发育中的功能。