Differential expression of CRP40 protein and its affects on dopamine-dependent behaviours and dopamine-activity

儿茶酚胺是一种神经递质，存在于外周和中枢神经系统(CNS)。中枢儿茶酚胺由多巴胺(DA)及其两种羟化产物去甲肾上腺素和肾上腺素组成。DA约占大脑中儿茶酚胺的80%，通过对特定受体的作用，是行为中重要的神经化学介质。同样，DA活性的异常也与异常行为有关。重要的是，DA在这些区域的作用是活动依赖的，并与突触中的细胞外DA水平紧密耦合。然而，人们对调节DA水平的分子机制知之甚少。这项拟议的研究计划旨在调查40 kDa儿茶酚胺调节蛋白(CRP40)在控制DA水平以及反过来控制DA依赖行为方面的作用。鉴于我的实验室已经证明CRP40是一种具有儿茶酚胺结合功能的多功能蛋白质，这一研究路线很有趣。此外，在存在过量DA活性的情况下，CRP40可能起到清除分子的作用。可以说，这些过程中的每一个都是DA整体调控的潜在组成部分，并支持CRP40对CNS DA水平产生根本性影响，从而对DA依赖行为产生影响的说法。然而，缺少的是旨在实验测试CRP40操纵对引起DA浓度变化的多巴胺能分子的影响以及DA依赖行为的研究，以阐明这些假定的潜在关系。这项研究计划中建议的方法将涉及大鼠大脑区域特异性的CRP40 mRNA的敲除，以研究CRP40敲除和恢复的时间过程如何与几个DA依赖行为的变化相关联。基于CRP40调节DA活性的假设，我们预测，DA依赖行为的功能障碍和恢复将遵循CRP40蛋白恢复的时间进程。

Catecholamines are neurotransmitters found in both the peripheral and central nervous system (CNS). CNS catecholamines consist of dopamine (DA) and its two hydroxylated products, norepinephrine, and epinephrenine. DA constitutes approximately 80% of catecholamines in the brain and, via its effects on specific receptors, is an important neurochemical mediator in behaviours. Likewise, aberrations in DA activity have been implicated in abnormal behaviour. Importantly, DA's effect in these domains is activity dependent and tightly coupled to extracellular DA levels in the synapse. However, relatively little is known about the molecular mechanisms that regulate levels of DA. The proposed research program seeks to investigate the role of a 40kDa catecholamine regulating protein (CRP40) in governing DA levels and, in turn, DA-dependent behaviour. This line of investigation is interesting given that my lab has shown that CRP40 is a multifunctional protein with catecholamine binding functions. Moreover, CRP40 may act as a scavenging molecule in the presence of excess DA activity. Arguably, these processes each represent potential components in the overall regulation of DA and bolster the suggestion that CRP40 has a fundamental impact on CNS DA levels and, consequently, DA-dependent behaviour. What is missing, however, are studies aimed at experimentally testing the impact of CRP40 manipulations on dopaminergic molecules causing alterations on DA concentrations, and DA-dependent behavior in order to elucidate these putative underlying relationships. The proposed approach in this research program will involve rat brain region specific knock-down of CRP40 mRNA in order to examine how the time-course of CRP40 knockdown and recovery is coupled to changes in several DA-dependent behaviours. Based on the hypothesis that CRP40 regulates DA activity, we predict that dysfunction and recovery of DA-dependent behaviours will follow the time-course of CRP40 protein recovery.