5-HT1A receptor anti-apoptotic transduction pathways in suicide

自杀中的5-HT1A受体抗凋亡转导途径

• 批准号: 8716851
• 负责人: Victoria Arango
• 金额: $ 26.51万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716851
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenylate Cyclase; Adult; Affect; Age; Anterior; Antibodies; Anxiety; Apoptotic; Area; Attenuated; Autopsy; BCL2 gene; BIRC4 gene; Biochemical; Biological; Biological Assay; Brain; Brain region; Cause of Death; Cell Death; Cell Density; Cell Survival; Cell physiology; Cerebellar cortex structure; Cerebellum; Cessation of life; Characteristics; Chromosomes, Human, Pair 10; Control Groups; Coupled; Coupling; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP-Responsive DNA-Binding Protein; Data; Defect; Depressed mood; Depression and Suicide; Development; Diagnosis; Disease; Disease susceptibility; Dorsal; Drug Targeting; Event; GTP-Binding Proteins; Health; Hippocampus (Brain); Homeostasis; Individual; Knockout Mice; Life; Link; Lipids; Major Depressive Disorder; Measurable; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Mitogen-Activated Protein Kinases; Mutant Strains Mice; Neurobiology; Neuroglia; Neurons; Occipital lobe; PTEN gene; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Prefrontal Cortex; Process; Protein Subunits; Proteins; Proto-Oncogene Proteins c-akt; Psychiatric Diagnosis; Receptor Activation; Receptor Signaling; Relative (related person); Role; Schizophrenia; Second Messenger Systems; Serotonin; Serotonin Receptor 5-HT1A; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Signaling Protein; Smoking Status; Suicide; Testing; Tissues; Triplet Multiple Birth; United States; Validation; attenuation; brain cell; cell type; cingulate cortex; density; depression prevention; early childhood; executive function; inhibitor/antagonist; insight; mood regulation; mutant; neuron loss; novel; protein expression; receptor function; response; restraint; second messenger; sex; suicidal behavior; suicidal morbidity; suicide brain; suicide victim; transcription factor

The 5-HT1A receptor is implicated in the pathology of anxiety, major depression and suicide. Studies with mutant mice indicate that the 5-HT1A receptor is necessary for the long-term viability of brain networks. Preliminary studies suggest that the activation of signaling molecules downstream of the 5-HT1A receptor is attenuated in the occipital cortex (OC) of suicides. We will determine whether this attenuation of signal transduction pathways is a characteristic of major depression or related to the diathesis for suicide by comparing suicides with major depression (MDD) to suicides with schizophrenia (SZ) and to nonpsychiatric, nonsuicide controls. We will evaluate four brain regions, one where we have found changes in both major depression and suicide (ventral prefrontal cortex, vPFC) and three regions where the findings seem more specifically linked to major depression (anterior cingulate cortex [ACC], dorsolateral PFC [BA9] and hippocampus). We predict signal transduction effects related to suicide will be present in both suicide groups and confined to the vPFC. We would predict the signal transduction changes related to MDD will be found in the MDD suicide group and not the other two groups and in the ACC and dorsal prefrontal cortex. We will test the hypothesis that 5-HT1A receptor-activated transduction pathways linked to cell survival are downregulated in specific brain regions relevant to major depression or for suicide. We will measure signaling proteins downstream of 5-HT1A receptors that are regulated via coupling to Gi/o and Gsubunits. One pathway involves the Gai-mediated inhibition of adenylyl cyclase (AC) and protein kinase A (PKA). The 5-HT-dependent inhibition of AC is normally counterbalanced by the concomitant activation of cell survival pathways. We propose that the reduced inhibition of AC in suicides represents a mechanism to counteract the reduction in the activity of the transduction pathways activated via the Gbg subunit. Investigating 5-HT1A receptor activation of NFkB, PI3-K/Akt and ERKs in suicide will advance our understanding of the role of 5-HT1A receptor signal pathways in depression and suicidal behavior. The cerebellar hemisphere will serve as a control region. We will also measure neuronal density, the levels of pro-apoptotic signaling molecules and death effectors. We hypothesize that the viability or functionality of brain cells that express 5-HT1A receptors is ¿neuroendangered¿ in major depression or suicide. Unraveling these events biochemically will yield crucial insights into the neurobiology of depression and suicide, major mental health problems in the US and the world. It may also identify novel drug targets for the treatment of depression and for the prevention of suicide. Suicidal behavior is a major health problem in the United States and the world. With 30,000 deaths by suicide per year in the US, suicide is the 11th leading cause of death. We have data indicating that the neuroprotective cellular pathways associated with the serotonin 1A receptor are altered in suicide. We want to explore this further by studying these pathways in various brain regions of suicides (depressed and schizophrenic) and normal controls. We hope to gain insight into the neurobiology of suicide versus depression and identify novel drug targets for treatment of depression and prevention of suicide.

在动画，严重抑郁和自杀的病理中暗示了5-HT1A受体。研究 突变小鼠表明5-HT1A受体对于脑网络的长期生存能力是必需的。 初步研究表明，5-HT1A受体下游信号分子的激活是 自杀的枕皮层（OC）减弱。我们将确定信号的衰减是否 转导途径是严重抑郁症的特征，或与自杀的素质有关 将自杀与严重抑郁（MDD）与精神分裂症（SZ）和非精神病学的自杀进行比较 非固定剂对照。我们将评估四个大脑区域，一个大脑区域都发现了两个主要区域 抑郁和自杀（腹前额叶皮层，VPFC）和发现似乎更多的三个区域 特别与重度抑郁症（前扣带回皮层[ACC]，托管PFC [BA9]和 海马）。我们预测两个自杀组将存在与自杀有关的信号转导影响 并局限于VPFC。我们将预测将在 MDD自杀组，而不是其他两个组，在ACC和背前皮层中。我们将测试 与细胞存活相关的5-HT1A受体激活转移途径的假设下调了 在与重大抑郁症或自杀有关的特定大脑区域中。我们将测量信号蛋白 5-HT1A接收器的下游通过耦合到gi/o和gsubunits进行调节。一条路 涉及GAI介导的抑制腺苷酸环化酶（AC）和蛋白激酶A（PKA）。 5-HT依赖性 AC的抑制通常与细胞存活途径的同时激活相抵消。我们 提议自杀中AC抑制减少的提议代表了抵消减少的机制 通过GBG亚基激活的转移途径的活性。研究5-HT1A受体激活 NFKB，pi3-k/akt和自杀中的erks将提高我们对5-HT1A接收器信号的作用的理解 抑郁和自杀行为的途径。小脑半球将用作对照区域。我们 还将测量神经元密度，促凋亡信号分子的水平和死亡效应。我们 假设表达5-HT1A受体的脑细胞的活力或功能是 在严重抑郁或自杀中神经倾向。在生化上阐明这些事件将产生至关重要的 对抑郁和自杀的神经生物学的见解，美国和美国的主要心理健康问题 世界。它还可以确定用于治疗抑郁症和预防自杀的新型药物靶标。自杀行为是美国和世界的主要健康问题。自杀30,000人死亡 在美国，自杀是第11大死亡原因。我们有数据表明神经保护 与5-羟色胺1A受体相关的细胞途径在自杀中改变。我们想探索这个 进一步研究自杀的各个大脑区域（抑郁和精神分裂症）和 正常对照。我们希望深入了解自杀与抑郁的神经生物学并确定新颖 治疗抑郁和预防自杀的药物靶标。