Perturbed cell signaling network and suicide neurobiology

扰动的细胞信号网络和自杀神经生物学

• 批准号: 9123677
• 负责人: Yogesh Dwivedi
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-12 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9123677
• 关键词: 70-kDa Ribosomal Protein S6 Kinases; Acetylation; Affinity; Apoptosis; Apoptotic; Area; Attention; Autopsy; BDNF gene; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; CASP3 gene; CREB1 gene; Caliber; Cause of Death; Cell Nucleus; Cell Survival; Cerebellum; Characteristics; Cleaved cell; Clinical; Cytosol; DNA Fragmentation; Dendrites; Depressed mood; Disease susceptibility; FOS gene; FRAP1 gene; Family history of; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Health; Hippocampus (Brain); Histones; Intervention; JUN gene; Lead; Length; Link; MAPK3 gene; MAPK8 gene; Major Depressive Disorder; Mediating; Mitogen-Activated Protein Kinases; Mitogens; Modification; Molecular; Morphology; NGFR Protein; NTRK2 gene; Neurobiology; Neuronal Plasticity; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nuclear; Pathway interactions; Peripheral; Personality; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Polyribosomes; Prefrontal Cortex; Prevalence; Prevention approach; Proteins; Psychiatric Diagnosis; Public Health; RPS6KA gene; Reporting; Ribosomal Protein S6 Kinase; Role; Sampling; Scaffolding Protein; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Site; Stress; Suicide; Suicide attempt; Suicide prevention; Surface; Synapses; System; TP53 gene; Tail; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Therapeutic Intervention; Tissues; To specify; Transactivation; Translations; United States; Vertebral column; activating transcription factor 1; age group; base; chromatin immunoprecipitation; chromatin remodeling; density; design; eIF-4B; genetic regulatory protein; mRNA capping; neuron apoptosis; neurotrophic factor; novel; overexpression; postsynaptic; protective effect; psychologic; psychosocial; relating to nervous system; scaffold; suicidal behavior; suicide brain; trait; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Suicide is a major public health concern. Suicidal behavior occurs in the context of a diathesis that is characterized by traits in multiple domains: behavioral, clinical, personality, and biologic. While the complexity of suicidal behavior requires a multi-faceted prevention approach, the identification of neurobiological dysfunction is critical for the pharmacological interventions that may have protective effects against suicidal behavior. In this context, we have shown reduced BDNF gene expression and less activation of its cognate receptor TrkB in the brain of suicide subjects. In addition, we have found that p75NTR, a low affinity BDNF receptor is upregulated in the brain of these subjects. BDNF, which plays a critical role in neural plasticity and cell survival, essentially mediates its action via TrkB-mediated activation of extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide 3 kinase (PI3K) signaling pathways. Abnormalities in these two signaling systems at the upstream levels were also found in the same brain areas of suicide subjects in which abnormalities were noted in BDNF/TRKB/p75NTR. These changes were present in all suicide subjects regardless of psychiatric diagnosis. To better understand the functional significance of altered BDNF signaling at molecular and cellular levels and their implications in the neurobiology of suicide, we propose to test the hypothesis that hypoactive BDNF/TrkB-mediated ERK1/2 and PI3K/Akt and overexpressed p75NTR will lead to modifications in the interaction and activation of downstream scaffolding/regulatory proteins, translational machinery, chromatin remodeling, and structural plasticity in the suicide brain. To test our hypothesis, in brain areas implicated in suicidal behavior, i.e., dlPFC and hippocampus (cerebellum as negative control brain region) from well-characterized and well-matched depressed suicide and non-psychiatric control subjects (n = 30 in each group), we aim to examine whether: 1) hypoactive ERK1/2 will lead to altered activation of substrates p90 ribosomal S6 kinase (RSK) and mitogen- and stress-activated kinase (MSK) and their mediated transactivation of transcription factors and chromatin remodeling; 2) hypoactive ERK1/2 and PI3K will lead to less active translational machinery, translation of postsynaptic genes, and altered dendritic morphology; and 3) altered PI3K/Akt and p75NTR will be associated with altered interactions of scaffolding proteins leading to c-Jun kinase (JNK) activation and altered expression and functional characteristics of downstream apoptotic regulatory proteins and neuronal apoptosis. To make sure that the effects are suicide specific, we will perform these studies in the same brain areas of an additional group of well-matched subjects who were depressed (no previous suicide attempt and no family history of suicide) and died by causes other than suicide (n = 30). Our proposed study will precisely and mechanistically assess the complexity of cellular signaling at the molecular, cellular, and functional levels in suicide brain and will have a significant impact in understanding not only the neurobiological basis of suicide but in designing more efficacious treatment strategies.

描述（由申请人提供）：自杀是一个主要的公共卫生问题。自杀行为发生在多个领域中特征的素质中的背景下：行为，临床，人格和生物学。虽然自杀行为的复杂性需要 一种多方面的预防方法，神经生物学功能障碍的鉴定对于可能对自杀行为具有保护作用的药理干预措施至关重要。在这种情况下，我们已经显示出BDNF基因表达降低，其同源受体TRKB在自杀受试者大脑中的激活降低。此外，我们发现P75NTR，低亲和力BDNF受体在这些受试者的大脑中被上调。 BDNF在神经可塑性和细胞存活中起关键作用，基本上通过TRKB介导的细胞外信号调节激酶（ERK）1/2的激活和磷酸辛酰胺3激酶（PI3K）信号途径介导了其作用。在上游水平的这两个信号系统中，在自杀受试者的相同大脑区域中也发现了异常，其中BDNF/TRKB/p75ntr中发现了异常。这些变化在所有自杀受试者中都存在，无论精神病诊断如何。为了更好地理解分子和细胞水平上BDNF信号传导改变的功能意义及其在自杀神经生物学中的影响，我们建议测试以下假设：低血压BDNF/TRKB介导的ERK1/2和PI3K/AKT和过度表达的P75NTR和c75ntr的互动率和激活率会导致互动和过度的互动术语，并导致互动的互动率和激活率自杀大脑中的翻译机制，染色质重塑和结构可塑性。 To test our hypothesis, in brain areas implicated in suicidal behavior, i.e., dlPFC and hippocampus (cerebellum as negative control brain region) from well-characterized and well-matched depressed suicide and non-psychiatric control subjects (n = 30 in each group), we aim to examine whether: 1) hypoactive ERK1/2 will lead to altered activation of substrates p90 ribosomal S6激酶（RSK）和有丝分裂原和应激激活激酶（MSK）及其介导的转录因子的反式激活和染色质重塑； 2）低连接性ERK1/2和PI3K将导致较少活跃的翻译机制，突触后基因的翻译和树突状形态的改变； 3）PI3K/AKT和P75NTR的改变将与导致C-JUN激酶（JNK）激活的脚手架蛋白的相互作用改变以及下游凋亡调节蛋白和神经元凋亡的表达和功能特征改变。为了确保特定的影响是自杀的，我们将在另外一组匹配的受试者组的相同大脑区域进行这些研究，这些受试者沮丧（没有以前的自杀企图，没有自杀的家族史），并死于自杀以外的其他原因（n = 30）。我们提出的研究将精确，机械地评估自杀大脑中分子，细胞和功能水平上细胞信号的复杂性 自杀的神经生物学基础，但在设计更有效的治疗策略时。