Molecular Determinants of Social Factors in Prostate Cancer

项目概要/摘要 题目：前列腺癌社会因素的分子决定因素 前列腺癌不成比例地影响非洲裔美国人（AA）男性， 和侵略性疾病。社会经济地位（SES）和社会压力，如邻里因素，广泛 被认为是这种健康差异的最主要驱动因素，然而， 应激和发病机制知之甚少。下丘脑-垂体-肾上腺轴 调节应激反应，并已被认为介导社会应激诱导的细胞 生理学种族差异在癌症的结果。HPA轴调节皮质醇水平控制糖皮质激素 (GC)社会压力后的反应。除了皮质醇，瘦素水平也被证明是 应激反应的影响因素。这种应激激素可以调节影响发病机制的细胞信号传导 和结果。microRNA是一种表观遗传元件，是高度稳定的非编码小21- 23 nt基因， 主要通过靶向3 'UTR起作用的调节RNA;已经研究了它们在癌细胞存活中的作用， 增殖和转移以及抗性和侵袭性PCa的生物标志物。我们最近 在PCa组织和体液（血清和尿液）中鉴定出种族不同的差异表达的miRNA， 潜在的生物标志物。糖皮质激素和瘦素信号传导均已显示影响 人类和实验室模型中的miRNAs。在这个建议中，我们将测试假设，社会和 邻里因素转化为持续的生物压力，扰乱压力激素的水平， 如皮质醇和瘦素，导致表观遗传机制的改变，包括miRNA的表达。的 一项提案将分析非裔美国人（AA）前列腺癌中的循环microRNA和应激激素水平 华盛顿特区都市区不同社会经济地位和社会压力的患者。接下来我们就 研究应激激素和选定的microRNA在调节癌症标志中的相互作用。最后， 我们将通过识别miRNA靶点和参与应激反应的途径来研究miRNA靶点-应激标记物， 机械地表征在社会压力期间调节的通路的所选miRNA。本研究将 通过研究逻辑表观遗传机制，弥合社会因素和生物决定因素之间的差距 受到社会压力的影响，造成健康差距。理解社会性行为的这些生物学意义 压力将显著影响非洲侵袭性前列腺癌诊断、预后和治疗进展 美国人

Project Summary/Abstract Title: Molecular Determinants of Social Factors in Prostate Cancer Prostate cancer disproportionately affects African American (AA) men with higher incidence, mortality and aggressive disease. Socioeconomic status (SES) and social stress such as neighborhood factors are widely regarded as the foremost driver of such health disparities however their association and translation to biological stress and mechanisms on pathogenesis are poorly understood. Hypothalamic-pituitary-adrenal axis (HPA) modulates stress response and has been suggested to mediate social stress induced effects on cellular physiology racial disparities in cancer outcomes. HPA-axis modulates cortisol levels controlling the glucocorticoid (GC) response following a social stress. In addition to cortisol, Leptin levels have been also demonstrated as effectors of stress response. Such stress hormones can modulate cancel cell signaling affecting pathogenesis and outcomes. MicroRNAs are epigenetic elements that are highly stable noncoding small 21-23nt gene- regulatory RNAs acting primarily by targeting 3’UTRs; their roles have been studied in cancer cell survival, proliferation, and metastasis as well as biomarkers of resistance and aggressive PCa. We have recently identified racially distinct differentially expressed miRNAs in PCa tissues and body fluids (serum and urine) as potential biomarker. Both Glucocorticoid and leptin signaling have been shown to affect the expression of miRNAs in human and laboratory models. In this proposal, we will test the hypothesize that social and neighborhood factors translate into continuous biological stress perturbing the levels of stress hormones such as cortisol and leptin resulting in alteration of epigenetic machinery including expression of miRNAs. The proposal will analyze circulating microRNAs and stress hormone levels in African American (AA) prostate cancer patients of the Washington DC metro area with differential socioeconomic status and social stress. Next, we will study the interplay between stress hormones and selected microRNAs in modulating cancer hallmarks. Finally, we will study miRNA-targets-stress markers by identifying miRNA targets and pathways involved to mechanistically characterize selected miRNAs for pathways modulated during social stress. This study will bridge the gap between social factors and biological determinants by studying logical epigenetic mechanisms modulated by social stress and causing health disparities. Understanding these biological implications of social stress will significantly impact diagnosis, prognosis and treatment development for aggressive PCa in African Americans.