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The aim of a present project is generation of new animal models of Parkinson's disease (PD) and their following characterization. The generation of new models is based on the recent knowledge about the genetic mechanisms of PD. It has been shown that the mutation of two genes, alpha-synuclein and parkin, causes familial PD. Therefore, we are planning to induce the targeted mutation of alpha-synuclein and parkin genes in mice. The conventional and conditional transgenic technology will be used for "knocking out" of alpha-synuclein and parkin genes. In the following stages we will characterize the phenotype of mice. This will start from the histological studies. After that the levels of dopamine and its metabolites will be measured in the striatum and mesencephalon, also the parameters of dopamine receptors will be studied in the subcortical structures. Moreover, the behavioural experiments will be performed in transgenic mice in order to study their motor functions. Also we will determine the ability of mice to learn in the novel situation. The behavioural effects of dopamine agonists and antagonists will be studied in these mice. Based on these studies we hope to develop the new models of PD more reliably reflecting the pathogenetic mechanisms in man. The development of these models will help us to design and study the new drugs for the medication of PD. |