Perturbed cell signaling network and suicide neurobiology

描述（由申请人提供）：自杀是一个主要的公共卫生问题。自杀行为发生在一种素质的背景下，这种素质的特点是多个领域的特征：行为，临床，人格和生物。虽然自杀行为的复杂性需要 作为一种多方面的预防方法，神经生物学功能障碍的识别对于可能对自杀行为具有保护作用的药物干预至关重要。在这种情况下，我们已经显示了减少BDNF基因表达和较少的激活其同源受体TrkB在自杀受试者的大脑。此外，我们发现p75 NTR，一种低亲和力的BDNF受体在这些受试者的脑中上调。BDNF在神经可塑性和细胞存活中起关键作用，其基本上通过TrkB介导的细胞外信号调节激酶（ERK）1/2和磷酸肌醇3激酶（PI 3 K）信号通路的活化来介导其作用。这两个信号系统在上游水平的异常也在自杀受试者的相同脑区中发现，其中BDNF/TRKB/p75 NTR异常。这些变化存在于所有自杀的受试者，无论精神病诊断。为了更好地理解BDNF信号在分子和细胞水平上改变的功能意义及其在自杀的神经生物学中的意义，我们建议检验以下假设：BDNF/TrkB介导的ERK 1/2和PI 3 K/Akt活性低下和p75 NTR过表达将导致下游支架/调节蛋白的相互作用和激活、翻译机制、染色质重塑、以及自杀大脑的结构可塑性为了验证我们的假设，在与自杀行为有关的大脑区域，dlPFC和海马（小脑作为阴性对照脑区），来自特征良好且匹配良好的抑郁自杀受试者和非精神病对照受试者（每组n = 30），我们的目的是检查是否：1）低活性ERK 1/2将导致底物p90核糖体S6激酶（RSK）和促分裂原和应激活化激酶（MSK）的活化改变2）ERK 1/2和PI 3 K活性低下将导致翻译机制、突触后基因翻译和树突形态改变;和3）改变的PI 3 K/Akt和p75 NTR将与支架蛋白的改变的相互作用相关，导致c-Jun激酶（JNK）活化和下游凋亡调节蛋白和神经元凋亡的改变的表达和功能特征。为了确保这些效应是自杀特异性的，我们将在另一组匹配良好的受试者的相同脑区进行这些研究，这些受试者患有抑郁症（以前没有自杀企图，也没有自杀家族史），死于自杀以外的原因（n = 30）。我们提出的研究将在分子、细胞和功能水平上精确地、机械地评估自杀脑中细胞信号传导的复杂性，不仅对理解自杀脑中的细胞信号传导有重要影响， 自杀的神经生物学基础，但在设计更有效的治疗策略。

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.