INTEGRINS IN DROSOPHILA LEARNING AND MEMORY

我的实验室的长期目标是了解细胞黏附分子在学习和记忆中的作用，重点是整合素。果蝇是这类研究的一个很好的模型系统，因为它强大的遗传学和在许多记忆范例中表现良好的能力。此外，由于参与学习和记忆的分子事件从苍蝇到小鼠都被很好地保守，利用果蝇的研究将继续提供关于行为可塑性基础分子事件的高度相关信息。此前，一种名为Volado的新果蝇嗅觉记忆突变体被分离出来。Volado苍蝇携带一种新的整合素α亚单位基因突变。整合素在学习和记忆中的作用还没有得到广泛的研究；然而，他们已经在许多其他过程中得到了研究。例如，整合素介导细胞-细胞以及细胞-基质的黏附，在发育、肿瘤转移和伤口愈合中发挥重要作用。虽然整合素的信号特性也得到了广泛的研究，但只鉴定了一小部分与整合素细胞质区域结合的蛋白质。因此，我们对整合素介导的记忆过程以及整合素介导的蛋白质-蛋白质相互作用的理解存在很大差距。在这一资助期间的主要目标之一将是确定与Volado基因产物物理上相互作用的必要的整合素Beta亚单位。这将通过分析携带候选贝塔亚基基因突变的动物的嗅觉记忆，确定贝塔亚基在成人中是否活跃或参与对嗅觉记忆至关重要的发育过程，以及探索Volado与其贝塔亚基之间的遗传和生化联系来实现。另一个主要目标将是利用有针对性的基因表达策略结合行为分析来描绘Volado和Beta亚单位活跃的大脑区域。此外，将通过分子和生化研究来探索直接与Volado的细胞质结构域及其β亚基结合的蛋白质的作用。总的来说，这些研究将确定与Volado基因产物相关的整合素β亚基，确定这两种蛋白必须在哪里表达才能发生正常记忆，并确定在行为可塑性中起整合素下游功能的候选蛋白。因此，拟议的研究将极大地增加我们对整合素在学习和记忆中所介导的分子和细胞过程的理解。

The long-term objective of my laboratory is to understand the role of cell adhesion molecules in learning and memory, with an emphasis on integrins. Drosophila is an excellent model system for such investigations because of its powerful genetics and ability to perform well in many memory paradigms. Additionally, since the molecular events involved in learning and memory are well conserved from flies to mice, studies utilizing Drosophila will continue to provide highly relevant information regarding the fundamental molecular events underlying behavioral plasticity. Previously, a new Drosophila olfactory memory mutant called Volado was isolated. The Volado fly carries a mutation in a novel integrin alpha subunit gene. Integrins have not been widely studied for their role in learning and memory; however, they have been examined in a number of other processes. For example, integrins mediate cell-cell as well as cell-substrate adhesion, and have important roles in development, tumor metastasis and wound healing. While the signaling properties of integrins have also been explored extensively, only a small number of proteins that bind to the cytoplasmic regions of integrins have been identified. Thus, there is a large gap in our understanding of integrin-mediated processes underlying memory as well as integrin-mediated protein-protein interactions in general. One of the major goals during this funding period will be to identify the requisite integrin beta subunit that physically interacts with the Volado gene product. This will be accomplished by analyzing olfactory memory in animals harboring mutations in candidate beta subunit genes, determining whether the beta subunit is active in the adult or participates in developmental processes important for olfactory memory, and exploring genetic and biochemical links between Volado and its beta subunit. Another major goal will be to delineate the brain regions in which Volado and the beta subunit are active using targeted gene expression strategies in combination with behavioral analyses. Additionally, the role of proteins that directly bind to the cytoplasmic domains of Volado and its beta subunit will be explored via molecular and biochemical studies. Collectively, these studies will identify the integrin beta subunit that associates with the Volado gene product, determine where these two proteins must be expressed for normal memory to occur, and identify candidate proteins that function downstream of integrins in behavioral plasticity. Thus, the proposed studies will add greatly to our understanding of the molecular and cellular processes mediated by integrins within the context of learning and memory.