Molecular Pathogenesis Of Cell Death In Neurodegenerativ

该项目的目标是阐明帕金森病神经细胞退化的分子机制，开发改进的治疗方法，并确定介导多巴胺能神经传递的基因的转录控制机制。帕金森病的特征是黑质致密部多巴胺能神经元进行性变性。在这种和许多其他神经退行性疾病中，一个基本的问题是大脑中独特的神经元群体的选择性脆弱性。在帕金森氏症的案例中，这似乎是多种因素的结果，但最明显的是黑质神经元产生了多巴胺递质。我们已经确定了多巴胺导致细胞凋亡性死亡的分子信号通路。这是因为多巴胺是一种有效的活性氧生成器，导致p38MAP激酶和JNK的激活，从而诱导细胞色素c从线粒体释放。随后，caspase 9被裂解(激活)，导致最终执行者caspase 3的激活。为了我们开发帕金森病新的治疗策略的目标，我们先前发现骨髓含有能够播种大脑和优先归巢到受损组织的细胞元件。我们现在试图利用这些细胞作为载体向大脑传递治疗性基因，即编码强大的多巴胺能神经营养因子神经胶质细胞系衍生神经营养因子(GDNF)的基因。我们证明了用GDNF工程细胞进行骨髓移植可以保护小鼠免受多巴胺能神经毒素MPTP的攻击。多巴胺通过其细胞表面受体发挥作用，这些受体受到复杂的空间和时间调节。我们发现了一种新的锌指转录因子，命名为DRRF(多巴胺受体调节因子)，它调节这些受体基因的表达。我们还确定了几种特定的转录因子相互作用，它们调节神经细胞中多巴胺受体基因的表达。例如，Zic2和Sp3抑制Sp1介导的D1A多巴胺受体启动子的激活，而TALE同源结构域蛋白Meis2和TGIF差异调节转录。

The goal of this project is to elucidate the molecular mechanisms by which nerve cells degenerate in Parkinson's disease, develop improved therapies and identify transcription control mechanisms of genes that mediate dopaminergic neural transmission. Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. A fundamental question in this and in many other neurodegenerative disorders is the selective vulnerability of unique neuronal populations in the brain. In the case of Parkinson's disease, this appears to be the result of multiple factors but most notably the production of the transmitter dopamine by nigral neurons. We have identified the molecular signaling pathway by which dopamine can result in apoptotic death. This is due to the fact that dopamine is an efficient generator of reactive oxygen species, leading to the activation of p38MAP kinase and JNK, which induce the release of cytochrome c from mitochondria. Subsequently, caspase 9 is cleaved (activated) leading to the activation of the final executor caspase 3. Towards our goal to develop novel therapeutic strategies for Parkinson's disease, we had previously found that the bone marrow contains cellular elements capable of seeding the brain and homing preferentially into injured tissue. We now sought to exploit these cells as vehicles to deliver a therapeutic gene to the brain, namely the genes that encodes the potent dopaminergic neurotrophic factor Glial Cell Line Derive Neurotrophic Factor (GDNF). We demonstrated that bone marrow transplantation with GDNF-engineered cells protects mice against the dopaminergic neurotoxin MPTP. Dopamine exerts its effects through its cell surface receptors, which are under complex spatial and temporal regulation. We found a novel zinc finger transcription factor, designated DRRF (Dopamine Receptor Regulatory Factor) which modulates the expression of these receptor genes. We also identified several specific transcription factor interactions that modulate the expression of dopamine receptor genes in neuronal cells. For example, Zic2 and Sp3 repress Sp1-mediated activation of the D1A dopamine receptor promoter and the TALE homeodomain proteins Meis2 and TGIF differentially regulate transcription.