(PQ3) AGEs and Race Specific Tumor Immune Response in Prostate Cancer

(PQ3) 前列腺癌中的 AGE 和种族特异性肿瘤免疫反应

基本信息

批准号：
8876216
负责人：
David Paul Turner
金额：
$ 14.04万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-06 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8876216
关键词：
Advanced Glycosylation End Products African American Age American Area Automobile Driving Biological Biological Markers Cancer Patient Carbohydrates Cardiovascular Diseases Cell Line Cells Cessation of life Chronic Community Outreach Cultured Tumor Cells DNA Development Diabetes Mellitus Diet Disease Education and Outreach Environment Environmental Risk Factor Epithelial Ethnic group European Exercise Failure Figs - dietary Gene Expression Generations Goals Growth HIF1A gene Health Human IL6 gene Immune Immune response Incidence Inflammation Inflammatory Inflammatory Response Interleukin-1 Lead Life Style Ligands Link Lipids Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Metabolism Minority Modeling Molecular Molecular Genetics Molecular Profiling Neurodegenerative Disorders Not Hispanic or Latino Nutritional Obesity Organ Outcome Pathway interactions Patients Pattern Play Population Production Prostatic Neoplasms Proteins Quality of Care Race Research Role STAT3 gene Signal Transduction Socioeconomic Factors Socioeconomic Status South Carolina Stromal Cells Surface Therapeutic Time Tissues Transcriptional Activation Tumor Biology Tumor Necrosis Factor-alpha Variant Work age group base cancer cell cancer health disparity cancer prevention cancer risk cell stroma cytokine defined contribution disease phenotype feeding glycation glycosylation health disparity immune activation in vivo men molecular phenotype mortality mouse model novel novel strategies overexpression prostate cancer cell prostate cancer cell line public health relevance racial and ethnic response sedentary lifestyle sugar transcription factor tumor tumor growth tumor initiation tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): AGEs and Race Specific Tumor Immune Response in Prostate Cancer African American (AA) prostate cancer patients are more likely to die of their disease than any other race or ethnic group in the US. Here in South Carolina (SC), age-adjusted prostate cancer incidence rates are 78% higher among AA men than EA men and mortality rates three times higher. While quality of care issues and socioeconomic status clearly contribute to cancer health disparities it is becoming increasing clear that molecular and genetic differences in tumor biology also play a critical role. Glycation is the non-enzymatic glycosylatio of sugars with proteins, lipids and DNA that lead to the production of reactive metabolites called advanced glycation end products (AGE's). AGEs accumulate in our tissues as we age to promote diseases associated with growing older such as diabetes and cardiovascular disease. Glycation occurs during normal metabolism but factors associated with cancer disparity such as poor diet and a lack of exercise significantly increase the accumulation of AGEs in our bodies. This study will conduct mechanistic research to investigate AGE accumulation as a biological consequence of the factors known to contribute to prostate cancer disparity. Our recent studies have led to our hypothesis that: "Race specific elevations in AGEs alter tumor associated immune responses in prostate cancer". AGEs function as a ligand activator for RAGE which is expressed on the surface of most immune cells. RAGE stimulation by AGE induces the transcriptional activation of a number of factors critical for the generation of an inflammatory environment including NFkB, STAT3 and HIF1a (4-6). Such activation results in the expression of immune associated cytokines such as IL1, IL6 and TNFa which are critical for mediating crosstalk between cancer cells and the stroma. Aim 1 will use primary and immortalized race specific cell line models to define the mechanistic implications of AGEs to the immune response. Aim 2 will use mouse models fed high and low AGE diets to determine the contribution of dietary AGEs to immune response and prostate cancer growth in vivo. The concept suggesting that AGE metabolites may represent a biological consequence of cancer disparity is a novel approach to explaining the increased incidence and mortality figures observed within specific populations. Associating the mechanistic links between glycation and altered immune response has also not been examined especially within the context of a race specific background or the prostate tumor microenvironment. By identifying a molecular consequence of cancer health disparity this study may contribute to reducing the cancer incidence and mortality rates among minority populations and identify novel potential biomarkers and define a novel area of therapeutic potential.

描述（由适用提供）：前列腺癌非裔美国人（AA）前列腺癌患者的年龄和种族特异性肿瘤免疫反应比美国的任何其他种族或族裔更有可能死于疾病。在南卡罗来纳州（SC），AA男性的年龄调整后的前列腺癌发病率比EA男性高78％，死亡率高三倍。尽管护理问题的质量和社会经济状况显然有助于癌症健康分布，但越来越清楚的是，肿瘤生物学的分子和遗传差异也起着至关重要的作用。糖基化是糖基质的非酶糖基糖基糖基糖基糖基，蛋白质，脂质和DNA可导致称为高级糖基化终产物（年龄）的反应性代谢物的产生。随着年龄的增长，年龄会积聚在我们的组织中，以促进与糖尿病和心血管疾病等年龄较大有关的疾病。糖化发生在正常代谢期间，但与癌症差异相关的因素（例如饮食不良和缺乏运动）显着增加了我们体内年龄的积累。这项研究将进行机械研究，以研究年龄的积累，这是已知导致前列腺癌差异的因素的生物学结果。我们最近的研究导致了我们的假设：“年龄段的种族特异性升高改变了前列腺癌中相关的肿瘤免疫复杂”。年龄充当愤怒的配体激活剂，在大多数免疫小球的表面表达。按年龄刺激的愤怒刺激引起了许多因素的转录激活，这对于包括NFKB，STAT3和HIF1A在内的炎症环境至关重要（4-6）。这种激活导致免疫增强响应细胞因子（例如IL1，IL6和TNFA）的表达对于介导癌细胞和基质之间的串扰至关重要。 AIM 1将使用原发性和永生的种族特定细胞系模型来定义AGES对免疫响应的机械意义。 AIM 2将使用喂养高年龄饮食的小鼠模型来确定饮食年龄对体内免疫增生和前列腺癌生长的贡献。该概念表明，年龄代谢物可能代表癌症差异的生物学后果是一种新的方法，可以解释在特定人群中观察到的增加的事件和死亡率数字。尤其在种族特定背景或前列腺肿瘤微环境的背景下，尤其是在糖基化和改变的免疫响应之间关联机械联系。通过鉴定癌症健康差异的分子后果，该研究可能有助于降低少数族裔人群的事件和死亡率，并确定新型潜在的生物标志物并定义了一种新型的治疗潜力领域。