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

项目摘要 这项拟议的研究的目的是确定与培养的保护作用有关的分子机制。 血压调节是阿拉斯加尤皮克原住民中风的主要危险因素。疾病的流行 美国印第安人和阿拉斯加原住民(AIAN)的中风发生率比美国其他任何种族/民族都要高 一群人。慢性心理压力会增加患高血压的风险，也是最常被提及的中风 AIAN人群中的危险因素。中风的患病率在过去的25年里有所增加，而且很可能 由包括历史创伤、文化变化和不利的社会经济在内的慢性应激源带来的 这反过来又增加了不健康的行为应对反应的可能性(例如，吸烟， 运动减少、睡眠不佳和暴饮暴食)。然而，我们之前的研究表明，两者都很强 对雅族文化传统(文化)的坚持与对雅族和白人文化的双重坚持 (双文化)与Yupik人相比，与坚持 更西式的生活方式(文化适应)。之前没有任何研究确定了导致这种现象的分子事件 灌输/双文化诱导的复原力(EBIR)对高血压风险的保护作用的基础， 这是发展旨在促进健康的文化有效干预措施的关键障碍。 这项拟议的研究考察了EBIR在应激-疾病级联反应的每一步中的作用-一个基于 关于将慢性应激事件与生物机制和疾病联系起来的广泛研究，如 高血压。我们假设EBIR阻止或缓冲了不利的个人和环境应激源 从而减少代谢功能障碍和炎症，抑制表观遗传失调，以及 维持白细胞端粒的长度，所有或部分会导致健康的血压。我们测试这些 通过解决以下特定目标(SA)进行假设：SA1-使用自我进行潜在类别分析 来自800名Yupik参与者的关于文化融入、双文化和慢性压力的报告数据，以组成班级 根据其EBIR/应激程度(SA1a)，然后评估EBIR/应激潜伏期之间的关系 班级与不适应健康相关行为以及血压之间的主要研究结果 测量(SA1b)；SA2-评估EBIR/应激潜伏期与代谢功能障碍之间的关联 (唾液皮质醇，空腹血糖和HbA1c水平，以及血脂水平)，线粒体不平衡负荷，以及 慢性低度炎症；和SA3-确定EBIR/应激潜伏期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(Sa3a)以及量化的关联 甲基化位点与血压(SA3b)之间的关系，并测试差异甲基化是否介导了 EBIR/应激潜伏期与血压之间的关系(SA3c)。我们还将评估白细胞 在每个EBIR/应激潜伏期(SA3d)中的个体之间的端粒长度，以便确定 EBIR减少了慢性应激对早熟端粒缩短的影响，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.