Toll-like Receptors and Cytokines in Depression and Suicide Brain

简介(申请人提供)：自杀是一个主要的公共卫生问题。仅在美国，每年约有3万人死于自杀，全世界约有100万人死于自杀。抑郁是自杀的主要危险因素。多项研究表明，S自杀还与神经生物学异常有关，如5-羟色胺功能和信号机制改变。一些研究还表明，抑郁症和自杀患者的免疫功能异常。这是基于对抑郁症和自杀患者血清和脑脊液中促炎症细胞因子水平的观察，以及对癌症患者给予细胞因子，如肿瘤坏死因子，引起与抑郁症相似的症状的观察，炎症细胞因子是免疫功能的主要媒介。最近的一些研究表明，抑郁症和自杀者大脑中的促炎细胞因子异常。细胞因子和趋化因子是免疫功能的重要生物介质。然而，似乎Toll样受体(TLR)可能是抵御病原体和组织损伤的第一道防线，也是天然免疫的主要介质。当被特定的配体激活时，TLRs诱导下游信号导致细胞因子和趋化因子的产生，这可以启动局部的炎症反应。为了研究细胞因子和TLRs在抑郁症和自杀中的作用，我们提议对抑郁症和自杀受试者死后脑中的TLRs、细胞因子和趋化因子进行全面的研究。拟议的研究也是基于我们的基因图谱研究的初步发现，该研究表明抑郁症自杀受害者的14个基因发生了改变(上调或下调)。这些改变的基因包括某些细胞因子、趋化因子和TLR。我们提出的研究的主要目标是详细检查自杀和抑郁大脑中特定的TLR和细胞因子基因的变化，以及这些变化是否与自杀(独立于诊断)有关，或者这些变化也是非自杀性抑郁症受试者所共有的。为了实现这一目标，我们将在四组受试者的背外侧前额叶皮质(DLPFC)和海马区进行基因谱研究，其中包括：1)正常对照组，2)抑郁自杀，3)非抑郁自杀，4)非自杀抑郁受试者。然后，我们将通过确定改变基因的mRNA和蛋白质表达来验证这些发现，我们发现在这些受试者中大约有14个基因。这些研究可能具有重要意义，因为它们可能导致确定抑郁症和自杀的重要生物标记和易损性标记，并可能为开发新的治疗药物提供有用的靶点，如TLR-3。这可能是首次对细胞因子、趋化因子和TLRs在抑郁症和自杀中的全面研究，对于了解抑郁症和自杀行为的病理生理学及其治疗具有重要意义。

DESCRIPTION (provided by applicant): Suicide is a major public health concern. About 30,000 people die each year by suicide in the USA alone, and about one million people die from it worldwide. Depression is a major risk factor for suicide. Several studies indicate that suicide s also associated with abnormal neurobiology, such as altered serotonin function and signaling mechanisms. Some studies also suggest abnormality of the immune function in depression and suicide. This is based on the observation of increased levels of proinflammatory cytokines, which are major mediators of immune function, in the serum and CSF of depressed and suicidal patients and the observation that administration of cytokines, such as TNF-¿, to cancer patients induces symptoms similar to those of depression. Some recent studies indicate abnormalities of proinflammatory cytokines in the brain of depressed and suicide subjects. Cytokines and chemokine are important biological mediators of immune function. However, it appears that Toll-like receptors (TLR), which may be the first line of defense against pathogens and tissue damage, are also major mediators of innate immunity. Upon activation by specific ligands, TLRs induce downstream signals that lead to cytokine and chemokine production, which can initiate a localized inflammatory response. In order to examine the role of cytokines and TLRs in depression and suicide, we are proposing a comprehensive study of TLRs, cytokines and chemokines in postmortem brain of depressed and suicide subjects. The proposed studies are also based on our preliminary findings from a gene profile study indicating alteration (up- or down-regulation) of 14 genes in depressed suicide victims. These altered genes include certain cytokines, chemokines and TLRs. The main objectives of our proposed studies are to examine in detail the specific TLR and cytokine genes that are altered in suicide and depressed brain, and if these altered genes are specific to suicide (independent of diagnosis) or these alterations are also shared by non-suicide depressed subjects. To achieve this objective we will conduct a gene profile study in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of four groups of subjects which include: 1) normal controls, 2) depressed suicide, 3) non-depressed suicide, 4) non- suicide depressed subjects. We will then validate these findings by determining the mRNA and protein expression of altered genes, which we find to be about 14 in these subjects. These studies may be significant as they may result in identification of important bio- and vulnerability markers for depression and suicide and may provide useful targets, such as TLR-3, for developing newer therapeutic agents. This may be innovative as it may be the first comprehensive study of cytokines, chemokines and TLRs in depression and suicide and is significant for understanding the pathophysiology of depression and suicidal behavior and its treatment.