5-HT1A receptor anti-apoptotic transduction pathways in suicide

自杀中的5-HT1A受体抗凋亡转导途径

基本信息

批准号：
8035275
负责人：
Victoria Arango
金额：
$ 42.72万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8035275
关键词：
1-Phosphatidylinositol 3-Kinase Adenylate Cyclase Adult Affect Age Anterior Antibodies Anxiety Apoptotic Area Attenuated Autopsy 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 Delivery Systems 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 Suicide prevention Testing Tissues Triplet Multiple Birth United States Validation attenuation brain cell cell type cingulate cortex density 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

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.

描述（由申请人提供）：5-HT1A 受体与焦虑、重性抑郁和自杀的病理有关。对突变小鼠的研究表明，5-HT1A 受体对于大脑网络的长期生存是必需的。初步研究表明，自杀者枕叶皮质 (OC) 中 5-HT1A 受体下游信号分子的激活减弱。我们将通过比较重度抑郁症（MDD）自杀者、精神分裂症（SZ）自杀者以及非精神病、非自杀对照者，确定这种信号转导途径的减弱是否是重度抑郁症的一个特征，或者是否与自杀素质有关。我们将评估四个大脑区域，其中一个区域我们发现了重度抑郁症和自杀的变化（腹侧前额叶皮层，vPFC），另外三个区域的研究结果似乎与重度抑郁症更具体相关（前扣带皮层 [ACC]，背外侧 PFC [ BA9]和海马体）。我们预测与自杀相关的信号转导效应将出现在两个自杀组中，并且仅限于 vPFC。我们预测，与 MDD 相关的信号转导变化将出现在 MDD 自杀组中，而不是其他两组以及 ACC 和背侧前额叶皮层中。我们将检验以下假设：与细胞存活相关的 5-HT1A 受体激活转导途径在与重度抑郁症或自杀相关的特定大脑区域中下调。我们将测量 5-HT1A 受体下游的信号蛋白，这些受体通过与 Gi/o 和 G 亚基偶联进行调节。其中一种途径涉及 Gai 介导的腺苷酸环化酶 (AC) 和蛋白激酶 A (PKA) 抑制。 AC 的 5-HT 依赖性抑制通常通过细胞存活途径的伴随激活来平衡。我们认为自杀中 AC 抑制的减少代表了一种抵消通过 Gbg 亚基激活的转导途径活性降低的机制。研究自杀中 NFkB、PI3-K/Akt 和 ERK 的 5-HT1A 受体激活将加深我们对 5-HT1A 受体信号通路在抑郁和自杀行为中的作用的理解。小脑半球将作为控制区域。我们还将测量神经元密度、促凋亡信号分子和死亡效应器的水平。我们假设表达 5-HT1A 受体的脑细胞的活力或功能在重度抑郁或自杀时会受到神经危害。从生物化学角度解开这些事件将为抑郁症和自杀的神经生物学以及美国和世界的主要心理健康问题提供重要的见解。它还可能确定治疗抑郁症和预防自杀的新药物靶点。公共卫生相关性：自杀行为是美国和世界的一个主要健康问题。美国每年有 30,000 人死于自杀，自杀是第 11 大死因。我们有数据表明，与 5-羟色胺 1A 受体相关的神经保护细胞通路在自杀过程中发生了改变。我们希望通过研究自杀者（抑郁症和精神分裂症患者）和正常对照组不同大脑区域的这些通路来进一步探索这一点。我们希望深入了解自杀与抑郁症的神经生物学，并确定治疗抑郁症和预防自杀的新药物靶点。