Depression, Stress, Aging & Proinflammatory Cytokines

描述(由申请人提供)：越来越多的证据表明，痴呆症家庭照料是影响心理和身体健康的一个风险因素。最近的研究证明，老年人中与护理和其他慢性应激源相关的各种健康风险背后的一个核心途径是：关键的促炎细胞因子白介素6(IL-6)持续过度生产。这项研究将在192名痴呆症配偶照顾者和192名社会人口统计学匹配的非照顾者对照中，研究参与5-羟色胺(5-HT)信号转运体(5-HTT)和5-HT1A受体的两种蛋白质的基因是否为抑郁和焦虑的易感基因。护理者样本的使用提供了一种方法，可以在明显处于危险之中的老龄化人口中复制和扩展关键的5-羟色胺易损性发现；此外，考虑到抑郁症与IL-6和肿瘤神经症因子-α(TNF-a)分泌增加之间的联系，我们还可以评估抑郁症的遗传易感性和关键促炎细胞因子的过度产生之间的联系。此外，这项研究将通过研究抑郁、焦虑和慢性应激对IL-6、CRP和TNF-a产生的影响，以及这三种标记的遗传变异对表达水平的影响，来扩大压力或抑郁与炎症标志物之间的已有文献记载的联系。因此，我们还将检查IL-6、肿瘤坏死因子-α和C反应蛋白的多态性，并评估不同组(非照顾者与照顾者、抑郁症与非抑郁者)中细胞因子水平的差异是否受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-HTT和5-HT1a受体是否代表照顾者和非照顾者对照组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组细胞因子表达水平与抑郁和焦虑关系的影响；3)确定照顾者、抑郁和焦虑症状的慢性应激、遗传易感性(5-HTT和5-HT1A的多态性)和遗传变异性(IL-6、CRP和TNF-a的多态性)对应激性生活事件发生后的前炎性反应的影响程度；4)确定年龄和痛苦对促炎细胞因子和C反应蛋白产生的交互作用。这项拟议的研究将扩大我们关于基因多态如何与环境应激源相互作用以增加不利心理和身体健康变化风险的知识。

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.