GATA2 as a therapeutic target in Parkinson's disease

描述（由申请人提供）：帕金森病（PD）与黑质（SN）中铁和1-突触核蛋白（1-syn）的病理性增加相关，这些特征是使用农药鱼藤酮复制的PD动物模型。1-syn和铁积累在黑质多巴胺神经元和细胞毒性，然而，其病理积累的机制是未知的。我们已经确定了转铁蛋白/转铁蛋白受体2（TfR 2）介导的黑质多巴胺神经元中铁积累的机制，并发现TfR 2水平在鱼藤酮大鼠多巴胺神经元中增加。加塔转录因子在造血中的作用已被充分表征，最近已显示其在体外正调控1-syn的表达。同种型GATA 2在人SN中表达，并且初步研究已经将GATA 2定位于大鼠SN中的多巴胺神经元。初步数据表明，GATA 2正调控TfR 2转录在体外。因此，这是可能的，GATA 2积极和协调调节1-syn和TfR 2在黑质多巴胺神经元在体内，和治疗GATA 2抑制可能同时改善PD的1-syn和铁的有害影响。该提案将在大鼠SN中使用体内病毒介导的基因沉默来测试以下假设：1）GATA 2调节大鼠黑质多巴胺神经元中的1-syn和TfR 2，以及2）在黑质多巴胺神经元中抑制GATA 2导致鱼藤酮处理后1-syn和铁的积累减少，从而减轻黑质纹状体变性。这项工作将研究如何两个明显不同的病理特征PD的1-突触核蛋白的积累和黑质多巴胺神经元内的铁的积累，可以协调衰减通过抑制转录因子，GATA 2，使用体内病毒介导的基因沉默。这些目标的成功完成将建立GATA 2作为一个潜在的治疗靶点，可以利用基因治疗来改善与人类PD中1-syn和铁积累相关的细胞毒性。 公共卫生相关性：帕金森病（PD）是一种神经退行性疾病，影响超过一百万美国人，目前没有治疗方法改变疾病进展。这项研究将评估特定的基因治疗干预是否通过同时作用于疾病的两个重要病理特征来预防脑变性。通过这项工作，可以确定一种最终用于人类PD临床的新型治疗干预措施，从而解决主要的公共卫生负担。

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is associated with pathological increases in iron and 1-synuclein (1-syn) in the substantia nigra (SN), and these features are reproduced animal models of PD that use the pesticide rotenone. Both 1-syn and iron accumulate in nigral dopamine neurons and are cytotoxic; however, the mechanism underlying their pathological accumulation is unknown. We have identified a transferrin/transferrin receptor 2 (TfR2)-mediated mechanism for iron accumulation in nigral dopamine neurons, and have found that TfR2 levels are increased in dopamine neurons in the rotenone rat. GATA transcription factors, whose role has been well characterized in hematopoiesis, have recently been shown to positively regulate the expression of 1-syn in vitro. The isoform GATA2 is expressed in human SN, and preliminary studies have localized GATA2 to dopamine neurons in rat SN. Preliminary data indicate that GATA2 positively regulates TfR2 transcription in vitro. Thus it is possible that GATA2 positively and coordinately regulates both 1-syn and TfR2 in nigral dopamine neurons in vivo, and that therapeutic GATA2 inhibition may simultaneously ameliorate the deleterious effects of both 1-syn and iron in PD. This proposal will use in vivo viral-mediated gene silencing in rat SN to test the following hypotheses: 1) GATA2 regulates 1-syn and TfR2 in rat nigral dopamine neurons, and 2) inhibition of GATA2 in nigral dopamine neurons leads to decreased accumulation of 1-syn and iron following rotenone treatment, thereby attenuating nigrostriatal degeneration. This work will examine how two apparently disparate pathological features of PD-the accumulation of 1-synuclein and the accumulation of iron within nigral dopamine neurons-may be coordinately attenuated via inhibition of the transcription factor, GATA2, using in vivo viral-mediated gene silencing. Successful completion of these aims would establish GATA2 as a potential therapeutic target that could be exploited using gene therapy to ameliorate the cellular toxicity associated with both 1-syn and iron accumulation in human PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is a neurodegenerative disorder that affects over one million Americans and currently no therapies alter disease progression. This research will evaluate whether a specific gene therapy intervention prevents brain degeneration by simultaneously acting on two important pathological features of the disease. A novel therapeutic intervention for eventual clinical use in human PD may be identified through this work, thereby addressing a major public health burden.