Glycation as a Mechanism Promoting Cancer Disparity

描述（由申请人提供）：糖基化是糖与蛋白质、脂质和DNA的非酶糖基化，导致称为晚期糖基化终产物（AGE’s）的反应性代谢物的产生。糖基化发生在糖过量的情况下，并导致许多与糖尿病相关的并发症。肿瘤还具有高葡萄糖水平的特征，这为能量生产提供了高速率的糖酵解（称为Warburg效应）。Project SuGAR是一个以社区为基础的研究数据库，关注受2型糖尿病影响的海岛家庭。本研究的目的是利用这一独特的资源及其储存的生物样本，探索高AGE代谢物水平是否能预测正常糖水平（非糖尿病岛民）和高糖水平（患有2型糖尿病的岛民）背景下的癌症发病率和死亡率。最近的研究证实了我们的假设，即“AGE- rage信号轴的激活促进了炎症，从而提高了AGE- rage水平，从而促进了癌症的差异”。本研究的具体目的1是将糖计划参与者中有和没有2型糖尿病的人的分泌AGE水平与癌症发病率和死亡率联系起来。这项初步研究首次分析了南卡罗来纳州海岛人口的癌症发病率和死亡率以及癌症/糖尿病共发病情况。衰老通过充当晚期糖基化终产物（RAGE）受体的配体介导许多有害影响。RAGE是一种促进炎症反应的致癌跨膜受体。分泌型RAGE （sRAGE）是RAGE的剪接变体，可作为诱骗结构域受体，减少RAGE在AGE细胞中的结合。在许多肿瘤类型中，较高的sRAGE水平与良好的预后相关。具体目标2将测量sRAGE以及炎症标志物的表达，与南卡罗来纳州海岛人口的AGE水平和癌症发病率和死亡率有关。对糖尿病和癌症之间的生物学联系的理解，由于缺乏潜在的共同风险因素的信息，尤其令人困惑。通过开发SuGAR项目中包含的现有数据集，包括癌症发病率和死亡率，我们将开发一个独特的资源，不仅可以解决这些混淆因素，还可以分析导致糖尿病、癌症和两种疾病合并症差异的种族特定因素。此外，age - rage -炎症信号轴可能作为预后/诊断标记具有潜在影响，可指导侵袭性疾病的治疗策略。它还可以定义一个新的治疗干预领域，可以在糖计划和海岛社区的临床试验中发展。非裔美国人患糖尿病和癌症的风险增加，并最终死于糖尿病和癌症。糖资源项目的发展和对糖基化在癌症中的作用的更深入的了解有可能显著影响这一人群的生存和生活质量。

DESCRIPTION (provided by applicant): Glycation is the non-enzymatic glycosylation of sugars with proteins, lipids and DNA that lead to the production of reactive metabolites called advanced glycation end products (AGE's). Glycation occurs whenever excessive sugars are available and drives many of the complications associated with diabetes. Tumors are also characterized by high glucose levels which fuels high rate glycolysis for energy production (known as the Warburg effect). Project SuGAR is a community based research database focusing on Sea Island families affected by type-2 diabetes. The goal of this study is to use this unique resource and its banked biological samples to explore if high AGE metabolite levels predict cancer incidence and mortality in a background of normal sugar levels (non-diabetic Sea Islanders) and high sugar levels (Sea Islanders with type-2 diabetes). Recent studies have led to our hypothesis that "elevated levels of AGE's promote cancer disparity through the activation of the AGE-RAGE signaling axis to promote inflammation". Specific aim 1 of this study relates secretory AGE levels to cancer incidence and mortality in Project SuGAR participants with and without type-2 diabetes. This initial study represents the first analysis of cancer incidence and mortality as well as cancer/diabetes co-morbidity within the Sea Island population of South Carolina. Ages mediate many of their deleterious effects by functioning as ligands for the receptor for advanced glycation end products (RAGE). RAGE is an oncogenic transmembrane receptor which promotes inflammatory responses. Secreted RAGE (sRAGE) is a splice variant of RAGE which can act as a decoy domain receptor to decrease AGE cellular binding of RAGE. Higher sRAGE levels are associated with favorable outcome in many tumor types. Specific aim 2 will measure sRAGE as well as inflammatory marker expression with which to relate to AGE levels and cancer incidence and mortality within the Sea Island population of South Carolina. Understanding biological links between diabetes and cancer is particularly confounded by the lack of information on potential shared risk factors. By developing the existing datasets contained within Project SuGAR to include cancer incidence and mortality rates, we will develop a unique resource to not only address these confounding factors but to analyze racial specific factors promoting disparity in diabetes, cancer and comorbidity for the two diseases. Additionally, the AGE-RAGE-inflammation signaling axis may have potential impact as prognostic/diagnostic markers to guide treatment strategies for aggressive disease. It may also define a novel area of therapeutic intervention which may be developed as clinical trials within Project SuGAR and the Sea Island community. African Americans have increased risk to develop and ultimately die of both diabetes and cancer. The development of the Project SuGAR resource and a greater understanding of the role of glycation in cancer have the potential to significantly impact survival and quality of life within this population.