RNA editing in suicide, major depression and animal model of depression

描述(申请人提供)：据估计，全球每年约有100万人死于自杀。自杀是导致死亡的主要原因之一，随着许多国家(包括美国)制定国家预防战略，自杀在世界范围内受到越来越多的关注。高达90%的自杀成年人至少有一种精神诊断(例如，严重抑郁障碍(MDD)、双相情感障碍(BPD)、精神分裂症(SZ))。目前尚不清楚自杀的生物学基础是否与共病精神障碍的生物学基础不同。在我们的初步研究中，我们检测了患有BPD或SZ并死于自杀或其他原因的人以及没有自杀的精神正常对照组的前额叶皮质(PFC)中5-HT2CR的mRNA编辑。我们检测到与自杀有关的编辑增加，但与精神诊断、人口统计特征、精神活性药物、酒精或药物滥用无关。基于这些发现，我们推测，信使核糖核酸编辑过程的改变可能是使个体倾向于自杀行为的因素之一。这项拟议的应用将进一步研究这一现象，以确定其在不同临床人群和不同大脑区域中的特异性，并阐明未来针对自杀行为的药物干预的分子靶点。我们最初的研究重点是患有BPD和SZ的人。然而，鉴于大多数自杀发生在MDD患者身上，如果不研究MDD背景下的5-HT2CR编辑，就不能牢固地建立这种现象对自杀行为的特异性的信心。此外，我们最初的研究是在控制决策和冲动的PFC中进行的。然而，自杀无疑有一个情感成分，我们将在拟议的应用程序中通过评估杏仁核和前扣带皮质的编辑来解决这一问题。这两个区域是参与情绪调节的皮质边缘回路的关键元素，在抑郁症中受到损害。为了从患者在疾病过程中服用药物引起的自杀中预期的5-HT2CR编辑变化中梳理出来，我们将使用暴露在不可预测的慢性轻度应激(UCMS)中的小鼠进行一项平行研究，这是一个在动物中研究抑郁症方面的已建立的模型。特别是，我们将调查UCMS暴露的小鼠在接受和不接受抗抑郁治疗时的编辑变化。编辑改变(如果观察到)将与在患有MDD和/或自杀的人类中检测到的改变进行比较。我们还将迈出第一步，阐明与自杀相关的编辑变异背后的分子机制。虽然5-HT2CR编辑受到许多不同因素的影响，但最明显的解释是编辑酶(作用于RNA或ADAR的腺苷脱氨酶)活性的变化。因此，我们将尝试评估ADAR在自杀和/或MDD中的活性。 公共卫生相关性：尽管与自杀相关的精神疾病的药物治疗有了显著改进，但在过去25年中，自杀率变化相对较小。只有了解了自杀的特定生物学机制，才能开发出有效的治疗自杀行为的药理学方法。根据我们最初的研究，其中一种自杀特异性机制可能源于信使核糖核酸编辑过程的改变。拟议中的应用将进一步研究这一现象，旨在阐明未来针对自杀行为的药物干预的分子靶点。

DESCRIPTION (provided by applicant): The estimated global burden of suicide is about one million deaths per year. Being one of the leading causes of death, suicide receives increasing attention worldwide, with many countries (including USA) developing national strategies for prevention. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis (e.g., major depressive disorder (MDD), bipolar disorder (BPD), schizophrenia (SZ)). Whether the biological underpinnings of suicide are distinct from those of the comorbid psychiatric disorders is unclear. In our "initial study" we examined mRNA editing of 5-HT2CR in the prefrontal cortex (PFC) of persons who had suffered from BPD or SZ and died by suicide or other causes as well as in psychiatrically normal controls without suicides. We detected an increase in editing that was associated with suicide but not with the psychiatric diagnoses, demographic characteristics, psychoactive medications, alcohol or drug abuse. Based on these findings, we hypothesize that an alteration in the mRNA editing process may be one of the factors that predispose individuals toward suicidal behavior. The proposed application will investigate this phenomenon further to establish its specificity among different clinical populations and different brain regions as well as to elucidate molecular targets for future pharmacological interventions against suicidal behavior. Our initial study was focused on persons with BPD and SZ. However, given that the majority of suicides occur in persons with MDD, confidence in specificity of this phenomenon for suicidal behavior cannot be firmly established without studying 5-HT2CR editing in the context of MDD. In addition, our initial study was performed in the PFC that control decision-making and impulsivity. However, there is undoubtedly an affective component to suicide, which we will address in the proposed application by assessing editing in the amygdala and the anterior cingulate cortex. These two regions are the crucial elements of the corticolimbic circuitries that are involved in mood regulation and that are compromised in depression. In an attempt to tease out the anticipated 5-HT2CR editing changes in suicide from those that are induced by medications taken by the patients in the course of the disease, we will perform a parallel study using mice exposed to the unpredictable chronic mild stress (UCMS), which is an established model to study aspects of depression in animals. In particular, we will investigate editing alterations in UCMS-exposed mice with and without antidepressant treatment. The editing alterations (if observed) will be compared to those detected in humans with MDD and/or suicide. We will also take a first step toward elucidating the molecular mechanisms underlying the suicide- associated variations in editing. Although 5-HT2CR editing is influenced by many different factors, the most obvious explanation is an alteration in the activity of the editing enzymes (adenosine deaminases that act on RNA or ADARs). Thus, we will attempt to assess the activity of ADARs in suicide and/or MDD. PUBLIC HEALTH RELEVANCE: Despite dramatic improvements in the pharmacological treatment of psychiatric disorders associated with suicide, there has been relatively little change in suicide rates over the past 25 years. Effective pharmacological approaches toward suicidal behavior can be developed only if biological mechanisms specific for suicide are understood. According to our initial study, one of those suicide-specific mechanisms may initiate from an alteration in the mRNA editing process. The proposed application will investigate this phenomenon further, aiming to elucidate molecular targets for future pharmacological interventions against suicidal behavior.