GATA2 as a therapeutic target in Parkinson's disease

GATA2作为帕金森病的治疗靶点

• 批准号: 7997685
• 负责人: MAX Parven HOROWITZ
• 金额: $ 4.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7997685
• 关键词: Address; Affect; American; Animal Model; Attenuated; Brain; Clinical; Data; Disease; Disease Progression; GATA2 transcription factor; Gene Silencing; Genetic Transcription; Hematopoiesis; Human; In Vitro; Intervention; Iron; Mediating; Neurodegenerative Disorders; Parkinson Disease; Pesticides; Protein Isoforms; Public Health; Rattus; Research; Role; Rotenone; Substantia nigra structure; Testing; Therapeutic; Toxic effect; Transferrin; Viral; Work; cytotoxic; dopaminergic neuron; gene therapy; in vivo; novel therapeutic intervention; prevent; public health relevance; synuclein; therapeutic target; transcription factor; transferrin receptor 2

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.

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) 的病理性增加有关，这些特征是使用杀虫剂鱼藤酮复制的 PD 动物模型。 1-syn 和铁均在黑质多巴胺神经元中积聚，具有细胞毒性；然而，其病理积累的机制尚不清楚。我们已经确定了转铁蛋白/转铁蛋白受体 2 (TfR2) 介导的黑质多巴胺神经元铁积累机制，并发现鱼藤酮大鼠多巴胺神经元中 TfR2 水平升高。 GATA 转录因子在造血过程中的作用已得到充分表征，最近已被证明可以在体外正向调节 1-syn 的表达。同工型 GATA2 在人类 SN 中表达，初步研究已将 GATA2 定位于大鼠 SN 中的多巴胺神经元。初步数据表明，GATA2 在体外正向调节 TfR2 转录。因此，GATA2 可能在体内积极协调地调节黑质多巴胺神经元中的 1-syn 和 TfR2，并且治疗性 GATA2 抑制可能同时改善 1-syn 和铁对 PD 的有害作用。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）GATA2 调节大鼠黑质多巴胺神经元中的 1-syn 和 TfR2，2）抑制黑质多巴胺神经元中的 GATA2 导致鱼藤酮治疗后 1-syn 和铁的积累减少，从而减弱黑质纹状体 退化。这项工作将研究如何利用体内病毒介导的基因沉默，通过抑制转录因子 GATA2 来协调减弱 PD 的两种明显不同的病理特征——1-突触核蛋白的积累和黑质多巴胺神经元内铁的积累。这些目标的成功完成将使 GATA2 成为一个潜在的治疗靶点，可以利用基因疗法来改善与人类 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，目前尚无治疗方法可以改变疾病进展。这项研究将评估特定的基因治疗干预是否可以通过同时作用于该疾病的两个重要病理特征来预防大脑退化。通过这项工作可能会确定一种最终临床用于人类帕金森病的新型治疗干预措施，从而解决重大的公共卫生负担。