Molecular Determinants of Social Factors in Prostate Cancer

项目摘要/摘要 前列腺癌社会因素的分子决定因素 前列腺癌对非裔美国人(AA)男性的影响不成比例，发病率、死亡率更高 和侵袭性疾病。社会经济地位(SES)和社会压力(如邻里因素)广泛存在 被认为是这种健康差距的最主要驱动因素，然而，它们之间的联系和转化为生物学 应激及其发病机制目前尚不清楚。下丘脑-垂体-肾上腺轴(HPA) 调节应激反应，并被认为介导社会应激对细胞的影响 癌症结局中的生理学种族差异。HPA轴调节控制糖皮质激素的皮质醇水平 (GC)社交压力后的反应。除了皮质醇，瘦素水平也被证明是 应激反应的效应器。这种应激激素可以调节影响发病的取消细胞信号。 和结果。MicroRNAs是一种表观遗传元件，是高度稳定的非编码小21-23nt基因。 调控RNA主要通过靶向3‘UTRs发挥作用；它们在癌细胞存活中的作用已被研究， 增殖、转移以及耐药和侵袭性前列腺癌的生物标志物。我们最近做了 在前列腺癌组织和体液(血清和尿液)中鉴定出种族差异表达的miRNAs为 潜在的生物标志物。糖皮质激素和瘦素信号都被证明影响 人类和实验室模型中的miRNAs。在这个提案中，我们将测试社会和 邻近因素转化为持续的生物应激，扰乱应激激素的水平，如 作为皮质醇和瘦素，导致表观遗传机制的改变，包括miRNAs的表达。这个 提案将分析非裔美国人(AA)前列腺癌患者的循环microRNA和应激激素水平 华盛顿大都会地区的患者具有不同的社会经济地位和社会压力。接下来，我们将 研究压力荷尔蒙和选定的microRNAs在调节癌症特征方面的相互作用。最后， 我们将通过确定miRNA靶标和参与的途径来研究miRNA靶标-应激标记。 从机械上表征在社会压力期间调节的通路的选定miRNAs。这项研究将 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 受到社会压力的调节，并造成健康差距。理解社会的这些生物学影响 应激将显著影响非洲侵袭性前列腺癌的诊断、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.