Toll-like Receptors and Cytokines in Depression and Suicide Brain

抑郁症和自杀脑中的 Toll 样受体和细胞因子

• 批准号: 8857262
• 负责人: Ghanshyam N Pandey
• 金额: $ 39.88万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857262
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Process; Autopsy; Biological; Brain; Brodmann' s area; Cancer Patient; Cause of Death; Cytokine Gene; Depressed mood; Depression and Suicide; Diagnosis; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Functional disorder; Gene Expression; Genes; Hippocampus (Brain); Hormones; Human; Immune; Immune system; Immunity; Inflammatory Response; Interleukin-1; Interleukin-6; Lead; Ligands; Mediator of activation protein; Mental Depression; Methods; Natural Immunity; Neurobiology; Neuroimmunomodulation; Neurons; Patient observation; Patients; Plasma; Prefrontal Cortex; Production; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Serotonin; Serum; Signal Transduction; Suicide; Symptoms; System; TNF gene; Teenagers; Therapeutic Agents; Time; Tissues; Toll-Like Receptor 2; Toll-like receptors; United States; Up-Regulation; Western Blotting; base; chemokine; cytokine; depressed patient; depression prevention; human TLR3 protein; immune function; innovation; mRNA Expression; novel therapeutics; pathogen; protein expression; suicidal; suicidal behavior; suicidal patient; suicide brain; suicide gene; suicide victim

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.

描述（由适用提供）：自杀是一个主要的公共卫生问题。仅在美国，每年大约有30,000人因自杀而死，大约有100万人死于全球。抑郁症是自杀的主要危险因素。几项研究表明，自杀也与神经生物学异常有关，例如羟色胺功能改变和信号传导机制。一些研究还表明，抑郁和自杀中免疫功能异常。这是基于观察到促炎细胞因子水平升高（是免疫功能的主要介体）在抑郁和自杀患者的血清和CSF中的主要介体，以及观察到癌症患者的施用类似于抑郁症的细胞因子（例如TNF-�）的给药。最近的一些研究表明，抑郁和自杀受试者大脑中促炎性细胞因子异常。细胞因子和趋化因子是免疫功能的重要生物学介质。然而，看来可能是针对病原体和组织损害的第一道防线的收费受体（TLR）也是先天免疫学的主要介体。特定配体激活后，TLR会诱导导致细胞因子和趋化因子产生的下游信号，从而引发局部炎症反应。为了检查细胞因子和TLR在抑郁和自杀中的作用，我们提出了一项对TLR，细胞因子和趋化因子和自杀受试者的事后大脑中的全面研究。拟议的研究还基于我们从基因谱研究​​中的初步发现，表明抑郁症违规中的14个基因的改变（上或下调）。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大脑抑郁症的特定TLR和细胞因子基因，如果这些改变的基因特异性针对自杀（独立于诊断），或者这些改变也会由非舒尼抑制受试者共享。为了实现这一目标，我们将对四组受试者的背外侧前额叶皮层（DLPFC）和海马进行一项基因概况研究，其中包括：1）正常对照，2）抑郁自杀，3）非抑郁自杀，4）4）非差不清的受试者。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，在这些受试者中我们发现它们约为14个。这些研究可能很重要，因为它们可能会导致抑郁症和自杀的重要生物和脆弱性标记，并可能为开发新的治疗剂提供有用的靶标，例如TLR-3。这可能是创新的，因为它可能是抑郁和自杀中细胞因子，趋化因子和TLR的首次全面研究，并且对于理解抑郁症和自杀行为及其治疗的病理生理学意义重大。