Reducing racial disparities in lung cancer outcomes by decoding neighborhood contextual environment (RECODE)

通过解码邻里环境来减少肺癌结果的种族差异 (RECODE)

• 批准号: 10402245
• 负责人: Sage J. Kim
• 金额: $ 65.59万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-06 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402245
• 关键词: Affect; African American; African American population; Area; Arginine; Behavioral; Biological; Biophysics; Black American; Black Populations; Cancer Etiology; Censuses; Cessation of life; ChIP-seq; Characteristics; Chicago; Chronic; Chronic stress; Cities; Clinical Trials; Communities; Computerized Medical Record; Cotinine; Crime; Data; Data Collection; Data Set; Disadvantaged; Distress; Economics; Environment; Environmental Risk Factor; Epigenetic Process; Epithelial; Exposure to; Frequencies; Gene Expression; Hair; Hydrocortisone; Immunohistochemistry; Incidence; Individual; Inflammatory Response; Link; Low Prevalence; Lung; Lung Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Methylation; Molecular; Morbidity - disease rate; Mus; Neighborhoods; Outcome; Patients; Physiological; Population; Protein Overexpression; Proteins; Research; Risk; Risk Factors; Sampling; Smoking; Smoking History; Social Conditions; Source; Stage at Diagnosis; Stress; Surveys; Testing; The Cancer Genome Atlas; Time; Tissue Sample; Transferase; United States; Violence; base; biobank; black men; cancer health disparity; cancer risk; cigarette smoking; contextual factors; high risk; improved; in silico; innovation; lung cancer screening; men; minority communities; mortality; novel; overexpression; prospective; protein expression; racial disparity; racial health disparity; racial minority; screening; screening guidelines; smoking exposure; social; social stress; social stressor; sociodemographics; socioenvironmental factor; systemic inflammatory response; transcriptome sequencing; violence exposure; violent crime

ABSTRACT This application proposes to examine a novel social epigenetic mechanism for racial inequality in lung cancer: Reducing racial disparities in lung cancer outcomes by decoding neighborhood contextual environment (RECODE). We will examine the relationships between exposure to violence, inflammatory responses, smoking and epigenetic changes in protein arginine methyl transferases (PRMT6) that increase the risk of developing lung cancer. Our preliminary studies demonstrated that smoking induces increased expression of PRMT6 in the lung epithelium. We also showed that overexpression of PRMT6 triggers spontaneous lung tumors in mice. Interestingly, we found that PRMT6 is upregulated among black men compared with white men in The Cancer Genome Atlas (TCGA). Thus we argue that the increased overexpression of PRMT6 among black men may explain a higher rate of lung cancer among black men compared with white men. While smoking is a key contributing factor for lung cancer, the frequency and amount of cigarette smoking are not necessarily higher for blacks, which suggests that other factors are responsible for racial disparity in lung cancer. Disproportionate social stress in black communities may be responsible for a higher rate of lung cancer among blacks. In particular, individuals living in excessive neighborhood violence are exposed to chronic stress, which may intensify the epigenetic changes for lung cancer. We hypothesize that exposure to neighborhood violence is social stress that increases biophysical inflammatory responses, which exacerbate the path between smoking, PRMT6 overexpression, and lung cancer. To examine the proposed social epigenetic mechanism of lung cancer disparity, first, we will test the independent effect of smoking and exposure to neighborhood violence, and the interaction of the two risks on PRMT6 expression using retrospective tissue samples from black and white lung cancer cases (Aim 2). Second, we will test the effect of exposure to violence on an inflammatory response (hair cortisol) and lung cancer screening outcomes by conducting a prospective survey and data collection with high-risk black men (Aim 3). Finally, we will build a multilevel, context-specific lung cancer risk profiles (Aim 1) that take into account not only individual behavioral risk (smoking), but neighborhood stress (exposure to violence), physiological inflammatory responses (increased cortisol), and molecular changes (PRMT6 overexpression). To develop such risk profiles, we utilize a composite population data approach to establish accurate counts of all individuals within census tracts with sociodemographic, behavioral, and neighborhood risk profiles. The strength of RECODE is its innovative approach to unveil a social epigenetic mechanism of lung cancer disparity. RECODE has the potential to transform understanding multilevel risks of lung cancer and improve the national lung cancer screening guidelines to reflect the social conditions of racial minority communities.

摘要 这项申请建议研究肺癌种族不平等的一种新的社会表观遗传机制： 通过解码邻里环境减少肺癌预后中的种族差异 (重新编码)。我们将研究暴露于暴力、炎症反应、 吸烟和蛋白质精氨酸甲基转移酶(PRMT6)的表观遗传学变化会增加患糖尿病的风险 患上肺癌。我们的初步研究表明，吸烟会导致血管紧张素转换酶基因表达增加。 肺上皮细胞表达PRMT6。我们还发现，PRMT6的过度表达会触发自发性肺 小鼠体内的肿瘤。有趣的是，我们发现与白人相比，PRMT6在黑人男性中表达上调 癌症基因组图谱中的男性。因此，我们认为PRMT6的过度表达增加 与白人男性相比，黑人男性患肺癌的几率更高。而当 吸烟是导致肺癌的关键因素，吸烟的频率和数量则不是。 对黑人来说必然更高，这表明其他因素也是导致肺部种族差异的原因 癌症。黑人社区中不成比例的社会压力可能是肺癌发病率较高的原因 黑人中的癌症。特别是，生活在过度邻里暴力中的个人暴露在 慢性应激，可能会加剧肺癌的表观遗传学变化。我们假设暴露在 邻里暴力是一种社会压力，它会增加生物物理炎症反应，从而加剧 吸烟、PRMT6过度表达和肺癌之间的关系。 为了研究肺癌差异的社会表观遗传机制，首先，我们将测试 吸烟和接触邻里暴力的独立影响，以及这两种风险对 使用黑人和白人肺癌患者的回顾性组织样本进行PRMT6的表达(目标2)。 其次，我们将测试暴露在暴力环境中对炎症反应(头发皮质醇)和肺的影响 对高危黑人男性进行前瞻性调查和数据收集的癌症筛查结果 (目标3)。最后，我们将建立一个多层次的、特定于背景的肺癌风险概况(目标1)，它将考虑到 不仅要考虑个人的行为风险(吸烟)，还要考虑邻居的压力(接触暴力)， 生理性炎症反应(皮质醇增加)和分子变化(PRMT6过度表达)。 为了建立这样的风险概况，我们利用综合人口数据方法来建立准确的 人口普查区域内具有社会人口、行为和邻里风险概况的所有个人。 Recode的力量在于它以创新的方式揭示了肺癌的社会性表观遗传机制 贫富差距。RECODE有可能改变对肺癌多水平风险的理解，并改善 国家肺癌筛查指南，以反映少数族裔社区的社会状况。