Glycation as a Mechanism Promoting Cancer Disparity

描述(申请人提供)：糖基化是糖与蛋白质、脂类和DNA的非酶糖基化，导致产生称为晚期糖基化终末产物(AGE‘s)的反应性代谢物。糖基化是在糖分过多的时候发生的，会导致糖尿病的许多并发症。肿瘤的特征还包括高血糖水平，这会加速糖酵解以产生能量(称为沃堡效应)。SIGH项目是一个以社区为基础的研究数据库，重点是受2型糖尿病影响的海岛家庭。这项研究的目的是利用这一独特的资源及其储存的生物样本来探索在正常血糖水平(非糖尿病的海岛人)和高糖水平(患有2型糖尿病的海岛人)的背景下，高年龄代谢物水平是否可以预测癌症的发病率和死亡率。最近的研究导致了我们的假设，即年龄水平的升高通过激活年龄-愤怒信号轴来促进炎症，从而促进癌症的差异。这项研究的具体目标1在患有和不患有2型糖尿病的项目糖参与者中，将分泌年龄水平与癌症发病率和死亡率联系起来。这项初步研究是对南卡罗来纳州海岛人口中癌症发病率和死亡率以及癌症/糖尿病共同发病率的首次分析。AGEs通过作为晚期糖基化终末产物受体(RAGE)的配基来调节其许多有害作用。RAGE是一种促炎症反应的致癌跨膜受体。分泌型RAGE(SRAGE)是RAGE的一个剪接变异体，可以作为诱骗结构域受体来降低RAGE与AGE细胞的结合。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，以与南卡罗来纳州海岛人口的年龄水平、癌症发病率和死亡率有关。由于缺乏关于潜在共同风险因素的信息，理解糖尿病和癌症之间的生物学联系尤其令人困惑。通过开发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杂因素，还可以分析导致糖尿病、癌症和两种疾病共病差异的种族特定因素。此外，年龄-愤怒-炎症信号轴可能作为预后/诊断标记物具有潜在的影响，以指导侵袭性疾病的治疗策略。它还可能定义一个新的治疗干预领域，该领域可发展为糖业计划和海岛社区内的临床试验。非裔美国人患糖尿病和癌症的风险增加，最终死于糖尿病和癌症。项目糖资源的开发和对糖基化在癌症中的作用的更好的了解，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.