Perturbed cell signaling network and suicide neurobiology

简介(申请人提供)：自杀是一个主要的公共卫生问题。自杀行为发生在以多个领域的特征为特征的素质的背景下：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。在此背景下，我们发现自杀受试者大脑中BDNF基因表达减少，其同源受体TrkB的激活程度降低。此外，我们还发现p75NTR是一种低亲和力的BDNF受体，在这些受试者的大脑中上调。脑源性神经营养因子在神经可塑性和细胞存活中起关键作用，主要通过TrkB介导的细胞外信号调节激酶(ERK)1/2和磷脂酰肌醇3激酶(PI3K)信号通路的激活来介导其作用。这两个信号系统在上游水平的异常也在自杀受试者的同一脑区被发现，其中BDNF/TrkB/p75NTR的异常被发现。这些变化在所有自杀受试者中都存在，无论精神诊断如何。为了更好地了解BDNF信号变化在分子和细胞水平上的功能意义及其在自杀神经生物学中的意义，我们建议检验以下假设：低活性的BDNF/TrkB介导的ERK1/2和PI3K/Akt以及高表达的p75NTR将导致自杀脑中下游支架/调节蛋白、翻译机制、染色质重塑和结构可塑性的相互作用和激活的改变。为了验证我们的假设，在特征良好且匹配良好的抑郁症自杀和非精神对照组受试者(每组30人)的dlPFC和海马区(小脑为阴性对照脑区)中，我们旨在检验：1)ERK1/2活性低下是否会导致底物P90核糖体S6激酶(RSK)和丝裂原和应激激活激酶(MSK)的激活改变，以及它们介导的转录因子和染色质重塑的反式激活；2)ERK1/2和PI3K活性低下将导致翻译机制不那么活跃，突触后基因的翻译和树突形态发生改变；3)PI3K/Akt和p75NTR的改变可能与导致c-Jun激酶(JNK)活化的支架蛋白相互作用改变、下游细胞凋亡调节蛋白和神经元凋亡的表达和功能特征改变有关。为了确保这些影响是自杀特有的，我们将在另外一组匹配良好的受试者的相同大脑区域进行这些研究，这些受试者患有抑郁症(既无自杀未遂，也没有自杀家族史)，并死于自杀以外的原因(n=30)。我们提出的研究将在分子、细胞和功能水平上准确和机械地评估自杀脑中细胞信号的复杂性，并将对理解自杀脑中的 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.