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

儿茶酚胺是存在于周围和中枢神经系统（CNS）中的神经递质。中枢神经系统儿茶酚胺由多巴胺（DA）及其两种羟基化产物，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%，通过其对特定受体的作用，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性依赖的，并且与突触中的细胞外DA水平紧密耦合。然而，调控DA水平的分子机制所知相对较少。拟议的研究计划旨在调查40kDa儿茶酚胺调节蛋白（CRP40）在控制DA水平中的作用，进而影响DA依赖行为。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，这条调查路线很有趣。此外，在存在过量DA活性的情况下，CRP40可能作为一种清除分子。可以说，这些过程各自代表了DA整体调控的潜在组成部分，并支持了CRP40对中枢神经系统DA水平和DA依赖行为具有根本影响的建议。然而，缺少的是旨在实验测试CRP40操作对多巴胺能分子的影响，从而导致DA浓度的改变，以及DA依赖行为，以阐明这些假定的潜在关系。本研究计划中提出的方法将涉及大鼠脑区域特异性敲除CRP40 mRNA，以研究CRP40敲除和恢复的时间过程如何与几种da依赖性行为的变化相耦合。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蛋白恢复的时间过程。

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.