Depression, Stress, Aging & Proinflammatory Cytokines

描述（由申请人提供）：越来越多的证据表明，痴呆症家庭护理是精神和身体健康的风险因素。最近的研究提供了与老年人护理和其他慢性压力源相关的各种健康风险背后的一个核心途径的证据：一种关键的促炎细胞因子-白细胞介素-6 （IL-6）的持续过量产生。本研究将探讨两种参与5-羟色胺（5-HT）信号传导的蛋白基因，即5-羟色胺转运体（5-HTT）和5-HT1A受体，是否在192名痴呆配偶照顾者和192名社会人口统计学匹配的非照顾者对照中成为抑郁和焦虑的易感基因。使用护理人员样本提供了一种方法来复制和扩展关键的5-羟色胺脆弱性研究结果与明显处于危险中的老龄化人口；此外，鉴于抑郁症与IL-6和肿瘤神经症因子- α (TNF-a)分泌增强之间的联系，我们还可以评估抑郁症的遗传易感性与关键促炎细胞因子过度产生之间的联系。此外，本研究将通过调查抑郁、焦虑和慢性压力对IL-6、CRP和TNF-a产生的影响，以及这三种标志物在表达水平上的遗传变异的影响，扩大压力或抑郁与炎症标志物之间的良好记录的关联。因此，我们还将检查IL-6、TNF-a和CRP的多态性，并评估不同组（无照顾者与照顾者、抑郁与无抑郁）中细胞因子水平的差异是否受到细胞因子基因型的影响，以及与年龄的关系。我们的具体目标是：1)确定5- httt和5-HT1A受体是否代表照顾者和非照顾者对照中抑郁和焦虑的易感基因；2)确定IL-6、CRP和TNF-a基因多态性对照顾者和非照顾者对照中细胞因子表达水平与抑郁、焦虑关系的影响；3)确定慢性护理压力、抑郁和焦虑症状、遗传易感性（5-HTT和5-HT1A多态性）和遗传变异性（IL-6、CRP和TNF-a多态性）对应激性生活事件发生后的促炎反应的影响程度；4)确定年龄和痛苦对促炎细胞因子和CRP产生的相互作用。这项拟议的研究将扩大我们对遗传多态性如何与环境压力因素相互作用以增加不良心理和身体健康变化风险的认识。

DESCRIPTION (provided by applicant): A growing body of evidence has implicated dementia family caregiving as a risk factor for mental and physical health. Recent work provides evidence of one core pathway behind the diverse health risks associated with caregiving and other chronic stressors among older adults: sustained overproduction of a key proinflammatory cytokine, interleukin-6 (IL-6). This study will address whether genes for two proteins involved in serotonin (5-HT) signaling, the 5-HT transporter (5-HTT) and the 5-HT1A receptor, are susceptibility genes for depression and anxiety in 192 dementia spousal caregivers and 192 sociodemographically-matched noncaregiver controls. Use of a caregiver sample provides a way to replicate and extend key 5-HT vulnerability findings with a aging population that is clearly at risk; moreover, given the links between depression and enhanced secretion of IL-6 and tumor neurosis factor-alpha (TNF-a), we can also assess ties between genetic vulnerability to depression and overproduction of key proinflammatory cytokines. Additionally, this study will expand the well-documented associations between stress or depression and markers of inflammation by investigating the effects of depression, anxiety, and chronic stress on production of IL-6, CRP, and TNF-a, as well as the effect of genetic variation in these three markers on expression levels. Thus, we will also examine polymorphisms for IL-6, TNF-a, and CRP, and assess whether the differences in cytokine levels among the various groups (noncaregivers vs. caregivers, depression vs. no depression) are influenced by the cytokine genotypes, as well as relationships with age. Our specific aims are: 1) to determine if 5-HTT and the 5-HT1A receptor represent susceptibility genes for depression and anxiety among caregivers and noncaregiving controls; 2) to determine the effects of polymorphisms in the genes for IL-6, CRP, and TNF-a on the relationship between cytokine expression levels and depression and anxiety in caregivers and noncaregiver controls; 3) to determine the extent to which the chronic stresses of caregiving, depressive and anxiety symptoms, genetic vulnerability (polymorphisms for 5-HTT and 5-HT1A), and genetic variability (polymorphisms for IL-6, CRP, and TNF-a) influence proinflammatory responses following the occurrence of stressful life events; and 4) to determine the interactive contributions of age and distress to proinflammatory cytokine and CRP production. The proposed study will expand our knowledge of how genetic polymorphisms interact with environmental stressors to enhance risk for adverse mental and physical health changes.