The impact of enculturation on the epigenetic relationship between chronic stress and hypertension in Yup'ik Alaska Native people

项目摘要 拟议研究的目的是确定文化保护作用的分子机制 血压调节是阿拉斯加Yup'ik土著人中风的主要危险因素。之时尚 美国印第安人和阿拉斯加原住民（AIAN）人群中的中风发生率高于美国任何其他种族/民族 组慢性心理压力会增加患高血压的风险，也是最常被引用的中风 AAN人群中的危险因素。在过去的25年里，中风的患病率有所增加， 由慢性压力源引起，包括历史创伤、文化变革和不利的社会经济因素 这些条件反过来又增加了不健康行为应对反应的可能性（例如，吸烟， 运动减少、睡眠不足和暴饮暴食）。然而，我们之前的研究表明， 坚持Yup'ik文化传统（文化融合）和双重坚持Yup'ik和白色文化 （双文化主义）与更健康的血压相关联时，Yup'ik个人坚持一个 文化适应（Acculturation）。以前的研究还没有确定潜在的分子事件， 文化融合/双文化诱导的复原力（EBIR）对高血压风险的保护作用的基础， 这是制定旨在促进健康的文化上有效的干预措施的一个关键障碍。 这项研究探讨了EBIR在压力-疾病级联反应的每一步中的作用， 广泛的研究将慢性压力事件与生物机制和疾病联系起来， 高血压我们假设EBIR阻断或缓冲不利的个人和环境压力源 导致减少代谢功能障碍和炎症，抑制表观遗传失调，和 维持白细胞端粒长度，其中全部或部分导致健康的血压。我们测试这些 通过解决以下具体目标（SA）的假设：SA 1-使用自我进行潜在类分析， 报告了来自800名Yup'ik参与者的关于文化融入、双文化主义和慢性压力的数据， 根据他们的EBIR/应激程度（SA 1a），然后评估EBIR/应激潜伏期之间的关系， 类和适应不良的健康相关行为以及血压之间的关系，主要研究结果 测量（SA 1b）; SA 2-评价EBIR/应激潜伏期类别与代谢功能障碍之间的关联 （唾液皮质醇、空腹血糖和HbA 1c水平以及脂质水平）、线粒体非稳态负荷，以及 慢性低度炎症;和SA 3-确定EBIR/应激潜伏类对表观基因组的影响- 广泛的DNA甲基化和下游基因表达的变化（SA 3a），以及量化相关性 之间的甲基化位点和血压（SA 3b），并测试是否差异甲基化介导的 EBIR/应激潜伏类与血压之间的关联（SA 3c）。我们还将评估白细胞 端粒长度在每个EBIR/应激潜伏类（SA 3d）中的个体之间，以确定是否 EBIR减少了慢性应激对端粒过早缩短的影响，端粒过早缩短是生物衰老的一个指标。

Project Summary The objective of the proposed research is to identify molecular mechanisms linking the protective role of culture to blood pressure regulation, a major risk factor for stroke in Yup'ik Alaska Native people. The prevalence of stroke is higher among American Indian and Alaska Native (AIAN) populations than in any other U.S. racial/ethnic group. Chronic psychological stress increases the risk for hypertension, and is the most frequently cited stroke risk factor in AIAN populations. The prevalence of stroke has increased over the past 25 years, and is likely brought on by chronic stressors including historical trauma, cultural change and adverse socioeconomic conditions which, in turn, increases the likelihood of unhealthy behavioral coping responses (e.g., smoking, reduced exercise, poor sleep and overeating). However, our previous research has shown that both strong adherence to Yup'ik cultural traditions (enculturation) and dual adherence to Yup'ik and White culture (biculturalism) are associated with healthier blood pressure when compared to Yup'ik individuals adhering to a more Western lifestyle (acculturation). No previous research has identified the molecular events underlying the basis for the protective effects of enculturation/biculturalism-induced resilience (EBIR) on risk for hypertension, representing a critical barrier to the development of culturally effective interventions aimed at promoting health. The proposed research examines the role of EBIR at each step of the stress-disease cascade – a model based on extensive research linking chronic stressful events to biological mechanisms and diseases such as hypertension. We hypothesize that EBIR blocks or buffers adverse individual and environmental stressors resulting in reduced metabolic dysfunction and inflammation, inhibition of epigenetic dysregulation, and maintenance of leukocyte telomere length, all or some of which lead to healthy blood pressure. We test these hypotheses by addressing the following Specific Aims (SAs): SA1 - Conduct latent class analysis using self- reported data about enculturation, biculturalism, and chronic stress from 800 Yup'ik participants to form classes based on their degree of EBIR/stress (SA1a), followed by evaluating the relationship between EBIR/stress latent classes and maladaptive health-related behaviors as well as between blood pressure, the main study outcome measure (SA1b); SA2 - Evaluate the association between EBIR/stress latent classes with metabolic dysfunction (salivary cortisol, fasting plasma glucose and HbA1c levels, and lipid levels), mitochondrial allostatic load, and chronic low-grade inflammation; and SA3 - Determine the impact of EBIR/stress latent classes on epigenome- wide DNA methylation and downstream changes in gene expression (SA3a) as well as quantify the association between methylation sites and blood pressure (SA3b), and test whether differential methylation mediates the association between EBIR/stress latent classes and blood pressure (SA3c). We will also evaluate leukocyte telomere length among individuals in each of the EBIR/stress latent classes (SA3d) in order to determine whether EBIR reduces the impact of chronic stress on premature telomere shortening, an indicator of biological aging.