Molecular Determinants of Social Factors in Prostate Cancer

前列腺癌社会因素的分子决定因素

• 批准号: 10369300
• 负责人: DEEPAK KUMAR
• 金额: $ 5.17万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-26 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369300
• 关键词: 3' Untranslated Regions; Academic Medical Centers; Affect; African American; Age; Apoptosis; Area; Back; Biological; Biological Markers; Body Fluids; Body mass index; Cancer Control; Cancer Patient; Caucasians; Cell Survival; Cell physiology; Cessation of life; Clinical; Complex; Consequentialism; Country; Data; Death Rate; Depressed mood; Diagnosis; Disease; District of Columbia; Drug resistance; Elements; Environment; Epigenetic Process; Exhibits; Fibrinogen; Glucocorticoids; Hormones; Human; Hydrocortisone; Incidence; Indolent; Laboratories; Leptin; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; MicroRNAs; Modeling; Molecular; Neighborhoods; Neoplasm Metastasis; Outcome; Pathogenesis; Pathway interactions; Patients; Physiological; Prognosis; Quality of life; RNA; Radiation therapy; Regulation; Regulator Genes; Resistance; Role; Sampling; Serum; Signal Transduction; Social Environment; Social isolation; Socioeconomic Status; Stress; Testing; Tissues; Translating; Translations; Untranslated RNA; Urine; Violence; base; biological adaptation to stress; cancer cell; cancer health disparity; castration resistant prostate cancer; circulating microRNA; cytokine; differential expression; driving force; epigenome; ethnic diversity; experience; health disparity; hypothalamic-pituitary-adrenal axis; inhibitor/antagonist; loss of function; men; miRNA expression profiling; mortality; potential biomarker; prostate cancer cell; prostate cancer metastasis; prostate carcinogenesis; racial disparity; response; segregation; social; social determinants; social factors; social implication; social stress; socioeconomics; stressor; therapy development; transcriptome; volunteer

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.

项目摘要/摘要 标题：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裔美国人（AA）男性，死亡率较高，死亡率 和侵略性疾病。社会经济地位（SES）和社会压力（例如邻里因素）广泛 被认为是这种健康差异的最重要的驱动力，但是它们的关联和转化为生物学 对发病机理的压力和机制知之甚少。下丘脑 - 垂体 - 肾上腺轴（HPA） 调节压力反应，并已提出媒体社会压力引起的对细胞的影响 癌症结局的生理种族差异。 HPA轴调节控制糖皮质激素的皮质醇水平 （GC）在社会压力下的反应。除皮质醇外，瘦素水平也被证明为 压力反应的影响。这种压力恐怖可以调节影响发病机理的取消细胞信号传导 和结果。 microRNA是表观遗传元素，它们是高度稳定的非编码小21-23NT基因 监管RNA主要是针对3'Utrs的；它们的作用已经在癌细胞存活中研究了， 增殖，转移以及抗性和侵略性PCA的生物标志物。我们最近有 在PCA组织和体液（血清和尿液）中鉴定出大致明显的miRNA，是 潜在的生物标志物。糖皮质激素和瘦素信号转导已证明会影响 人类和实验室模型中的miRNA。在此提案中，我们将测试假设的社会和 邻里因素转化为连续的生物压力，使压力激素的水平扰动这样 作为皮质醇和瘦素，导致表观遗传机制的改变，包括miRNA的表达。这 提案将分析非洲裔美国人（AA）前列腺癌的循环microRNA和压力同位水平 华盛顿特区都会区的患者具有不同的社会经济地位和社会压力。接下来，我们会的 在调节癌症标志中研究应力激素与选定的microRNA之间的相互作用。最后， 我们将通过确定涉及的miRNA目标和途径到 机械学表征了在社会压力期间调节的途径的选定miRNA。这项研究会 通过研究逻辑表观遗传机制来弥合社会因素和生物学决定性之间的差距 由社会压力调节并导致健康差异。了解社会的这些生物学含义 压力将显着影响非洲侵略性PCA的诊断，预后和治疗开发 美国人。