Treating Depression with Histone Deacetylase Inhibitors

用组蛋白脱乙酰酶抑制剂治疗抑郁症

• 批准号: 6927476
• 负责人: Schahram Akbarian
• 金额: $ 24.06万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6927476
• 关键词: acetylation; amidohydrolases; angiogenesis factor; antidepressants; behavior test; biological signal transduction; blood brain barrier; chromatin immunoprecipitation; clinical depression; drug screening /evaluation; enzyme inhibitors; genetic promoter element; hippocampus; histones; laboratory mouse; learned helplessness; mental disorder chemotherapy; neurotrophic factors; nonhuman therapy evaluation; pharmacogenetics; pharmacokinetics; polymerase chain reaction; psychopharmacology

DESCRIPTION (provided by applicant): Depression is considered one of the most serious disorders in today's society, with a lifetime prevalence as high as 16.2% in the US adult population. The introduction of the first pharmacological antidepressant medications in the 1950s, and subsequent development of drugs with lower side-effect profiles has greatly improved the therapeutic outlook for depressed patients. Notably, all the antidepressant drugs now in use modulate monoamine neurotransmission and take six to eight weeks to exert their effects. Still, treatment-resistant depression, which typically refers to inadequate response to at least one antidepressant trial of adequate dose and duration, affects up to 50-60% of patients. Therefore, it will be necessary to test and develop antidepressants with conceptually novel mechanisms of actions and a more rapid therapeutic response. The focus of this application is on pre-clinical studies to assess the antidepressant potential of a novel class of therapeutic drugs, historic deacetylase inhibitors (HDACi). Our central goals are to 1) find out if HDACi's that cross the blood-brain barrier alter test performance in rodent models for anxiety, behavioral despair and learned helplessness and 2) to study HDACi-induced chromatin-remodeling, including histone acetylation, at proximal promoter sequences of genes that are involved in neurotrophin and/or angiogenic-endothelial signaling pathways. The behavioral experiments (Aim #1) are guided by preliminary data demonstrating that mice treated for 14-16 days with the HDACi, sodium butyrate, show lower levels of behavioral despair, in comparison to controls. The chromatin studies (Aim #2) will rely on immunoprecipitation of hippocampal extracts with site- and modification-specific anti-histone antibodies, in conjunction with quantitative real time PCR for proximal promoter sequences and RT-PCR for coding sequences of 10 neurotrophic and angiogenic factors that are thought to play a role in the neurobiology or treatment of depression. It is expected that these novel approaches will provide promising first insights into the antidepressant potential of HDACi's and will establish the epigenetic modification of hippocampal chromatin as an important molecular mechanism for the neurobiology of depression.

描述（由申请人提供）：抑郁症被认为是当今社会中最严重的疾病之一，在美国成年人口中，终生患病率高达16.2％。在1950年代引入了第一种药理学抗抑郁药，并随后开发具有较低副作用的药物，极大地改善了抑郁症患者的治疗外观。值得注意的是，现在使用的所有抗抑郁药均使用调节单胺神经传递，并花费六到八周才能发挥作用。尽管如此，抗治疗抑郁症通常是指对至少一项适当剂量和持续时间的抗抑郁药试验的反应不足，最多影响50-60％的患者。因此，有必要通过概念上新颖的作用机理和更快的治疗反应来测试和开发抗抑郁药。该应用的重点是临床前研究，以评估一种新型治疗药物，历史性脱乙酰基酶抑制剂（HDACI）的抗抑郁潜力。我们的核心目标是1）找出越过血脑屏障的HDACI是否在啮齿动物，行为绝望和学习的无助模型中改变了测试性能，以及2）研究HDACI诱导的染色质蛋白复制层，包括组蛋白乙酰化，包括在近端基因启动基因的基因启动和或或或依赖神经蛋白的基因启动者。行为实验（AIM＃1）的指导是通过初步数据指导，表明用HDACI，丁酸钠治疗了14-16天的小鼠，与对照组相比，行为绝望水平较低。染色质研究（AIM＃2）将依赖于具有位点和修饰的特异性抗Histone抗体的海马提取物的免疫沉淀，并结合定量实时PCR，用于近端启动子序列和RT-PCR的RT-PCR，用于编码10个神经植物和血管生成因子的序列，这些神经植物和血管生成因子的抑制作用或抑制作用的作用。 可以预期，这些新颖的方法将为HDACI的抗抑郁潜力提供有希望的首先见解，并将建立海马染色质的表观遗传学修饰，作为抑郁症神经生物学的重要分子机制。