(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（由申请人提供）：前列腺癌中的 AGE 和种族特异性肿瘤免疫反应在美国南卡罗来纳州 (SC)，非洲裔美国人 (AA) 前列腺癌患者比任何其他种族或族裔群体更有可能死于该病。），根据年龄调整，AA 男性的前列腺癌发病率比 EA 男性高 78%，死亡率高出三倍。肿瘤生物学中的遗传差异也发挥着关键作用，糖化是糖与蛋白质、脂质和 DNA 的非酶糖基化，导致称为晚期糖基化终产物 (AGE) 的反应性代谢产物在我们的组织中积累。年龄促进与年龄增长相关的疾病，如糖尿病和心血管疾病，糖化发生在正常代谢过程中，但与癌症差异相关的因素，如不良饮食和缺乏运动，会显着增加我们体内 AGE 的积累。这项研究将进行机制研究，以调查 AGE 积累是已知导致前列腺癌差异的因素的生物学结果，我们最近的研究得出了我们的假设：“AGE 的种族特异性升高会改变前列腺癌中肿瘤相关的免疫反应”。 AGE 作为 RAGE 的配体激活剂发挥作用，RAGE 在大多数免疫细胞表面表达，AGE 刺激的 RAGE 会诱导许多对炎症环境产生至关重要的因子的转录激活，包括 NFkB、 STAT3 和 HIF1a (4-6) 会导致免疫相关细胞因子（例如 IL1、IL6 和 TNFa）的表达，这些细胞因子对于介导癌细胞和基质之间的串扰至关重要。Aim 1 将使用原代和永生化种族特异性细胞系。确定 AGE 对免疫反应的机制影响的模型目标 2 将使用高 AGE 和低 AGE 饮食喂养的小鼠模型来确定膳食 AGE 对体内免疫反应和前列腺癌生长的贡献。表明 AGE 代谢物可能代表癌症差异的生物学后果的概念是解释特定人群中观察到的发病率和死亡率增加的一种新方法。尤其是在癌症背景下，糖化和免疫反应之间的机制联系也尚未得到检验。通过确定癌症健康差异的分子后果，这项研究可能有助于降低少数群体的癌症发病率和死亡率，并确定新的潜在生物标志物并确定新的治疗潜力领域。