Toll-like Receptors and Cytokines in Depression and Suicide Brain

描述（由申请人提供）：自杀是一个主要的公共卫生问题。仅在美国，每年就有大约3万人死于自杀，全世界约有100万人死于自杀。抑郁症是自杀的主要危险因素。几项研究表明，自杀也与异常的神经生物学有关，如血清素功能和信号机制的改变。一些研究也提示抑郁症和自杀的免疫功能异常。这是基于在抑郁症和自杀患者的血清和CSF中观察到促炎细胞因子（免疫功能的主要介质）水平升高，以及对癌症患者给予细胞因子（如TNF-α）诱导类似于抑郁症的症状。最近的一些研究表明抑郁症和自杀受试者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，Toll样受体（TLR）可能是抵抗病原体和组织损伤的第一道防线，也是先天免疫的主要介质。在被特异性配体激活后，TLR诱导导致细胞因子和趋化因子产生的下游信号，这可以引发局部炎症反应。 为了研究细胞因子和TLR在抑郁症和自杀中的作用，我们建议对抑郁症和自杀受试者死后大脑中的TLR、细胞因子和趋化因子进行全面研究。这些研究也是基于我们从基因图谱研究中的初步发现，该研究表明抑郁症自杀者中14个基因的改变（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的是详细检查自杀和抑郁症的大脑中改变的特定TLR和细胞因子基因，以及这些改变的基因是否是自杀特异性的（独立于诊断），或者这些改变也被非自杀抑郁症受试者所共有。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层（DLPFC）和海马中进行基因谱研究，这四组受试者包括：1）正常对照，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，我们发现这些受试者中约有14个基因。这些研究可能是重要的，因为它们可能导致识别抑郁症和自杀的重要生物和脆弱性标志物，并可能为开发新的治疗药物提供有用的靶点，如TLR-3。这可能是创新的，因为它可能是第一个全面研究抑郁症和自杀中的细胞因子，趋化因子和TLR，对于理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.