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族成员是精神和身体健康的危险因素。最近的工作提供了一个核心途径背后的证据，与老年人中的吸烟和其他慢性压力源相关的各种健康风险：一种关键的促炎细胞因子，白细胞介素-6（IL-6）的持续过量生产。本研究将探讨两种参与5-羟色胺（5-HT）信号传导的蛋白质，即5-HT转运体（5-HTT）和5-HT 1A受体的基因是否是192名痴呆症配偶照顾者和192名社会人口学匹配的非照顾者对照的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-HT脆弱性发现与老龄化人口，这显然是在风险;此外，鉴于抑郁症和IL-6和肿瘤神经症因子-α（TNF-α）的分泌增强之间的联系，我们还可以评估遗传易感性抑郁症和关键促炎细胞因子的过度生产之间的联系。此外，这项研究将通过调查抑郁症，焦虑症和慢性应激对IL-6，CRP和TNF-α产生的影响，以及这三种标志物的遗传变异对表达水平的影响，扩展压力或抑郁症与炎症标志物之间的良好记录关联。因此，我们还将检查IL-6、TNF-a和CRP的多态性，并评估各组（非看护者与看护者、抑郁症与非抑郁症）之间细胞因子水平的差异是否受细胞因子基因型以及与年龄的关系的影响。我们的具体目标是：1）确定5-HTT和5-HT 1A受体是否代表照料者和非照料者对照中抑郁和焦虑的易感基因; 2）确定IL-6、CRP和TNF-α基因多态性对照料者和非照料者对照中细胞因子表达水平与抑郁和焦虑之间关系的影响; 3）确定在多大程度上，慢性应激的抑郁，焦虑症状，遗传易感性，（5-HTT和5-HT 1A的多态性）和遗传变异性（IL-6、CRP和TNF-α的多态性）影响应激性生活事件发生后的促炎反应;以及4）确定年龄和痛苦对促炎细胞因子和CRP产生的交互作用。这项拟议中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.