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，严重抑郁和自杀的病理有关。使用突变小鼠的研究表明，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，在自杀的枕叶皮层（OC）中，5-HT1A受体下游的信号分子的激活减弱。我们将确定信号转导途径的这种衰减是通过将重度抑郁症（MDD）与精神分裂症（SZ）和非精神病患者非精神病患者自杀的自杀和非精神病，非精神病，非精神病，非精神分裂症对照组的自杀的特征。我们将评估四个大脑区域，一个区域发现了重大抑郁症和自杀（腹前额叶皮层，VPFC）的变化，以及三个区域，这些区域似乎与重大抑郁症（前扣带盖皮层[ACC]，背侧外侧PFC [BA9]和Hampocampus）更具体相关。我们预测，两个自杀组都存在与自杀有关的信号转导影响，并局限于VPFC。我们将预测与MDD相关的信号转导变化将在MDD自杀组中发现，而不是其他两个组以及ACC和背额叶前皮层。我们将检验以下假设：与大抑郁症或自杀有关的特定大脑区域中，与细胞存活相关的5-HT1A受体激活的转导途径被下调。我们将测量5-HT1A受体下游的信号蛋白，这些蛋白通过与GI/O和Gsubunits耦合进行调节。一条途径涉及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。我们建议，自杀中AC的抑制减少代表了一种应对通过GBG亚基激活的转导途径的降低的机制。研究NFKB，PI3-K/AKT和ERK在自杀中的5-HT1A受体激活将提高我们对5-HT1A受体信号途径在抑郁和自杀行为中的作用的理解。小脑半球将用作对照区域。我们还将测量神经元密度，促凋亡信号分子和死亡效应子的水平。我们假设表达5-HT1A受体的脑细胞的生存力或功能在重大抑郁或自杀中神经构成。从生物化学上阐明这些事件将产生对抑郁和自杀，美国和世界重大心理健康问题的神经生物学的重要见解。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。公共卫生相关性：自杀行为是美国和世界的主要健康问题。在美国，每年自杀30,000人死亡，自杀是第11大死亡原因。我们有数据表明，与5-羟色胺1A受体相关的神经保护性细胞途径在自杀中发生了改变。我们希望通过研究自杀（抑郁和精神分裂症）和正常对照的各个大脑区域中的这些途径来进一步探讨这一点。我们希望深入了解自杀与抑郁症的神经生物学，并确定治疗抑郁和预防自杀的新药物。