Glycation as a Mechanism Promoting Cancer Disparity

糖化是促进癌症差异的机制

• 批准号: 8494770
• 负责人: David Paul Turner
• 金额: $ 19.49万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494770
• 关键词: Address; Admixture; Advanced Glycosylation End Products; Affect; Africa; African; African American; Age; Age of Onset; Area; Automobile Driving; Basic Cancer Research; Biological; Body Weight; Cancer Patient; Cancer Prognosis; Cessation of life; Chronic; Clinical Trials; Communities; Comorbidity; Complex; DNA; Data; Data Set; Databases; Development; Diabetes Mellitus; Diagnostic; Diet; Disease; Epidemiologic Studies; European; Factor Analysis; Family; Future; Genetic; Glucose; Glycolysis; Goals; Hyperglycemia; Incidence; Inflammation; Inflammatory; Inflammatory Response; Island; Lead; Life; Ligands; Link; Lipids; Lysine; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oncogenic; Outcome; Participant; Patients; Phenotype; Population; Predisposition; Production; Proteins; Quality of life; RNA Splicing; Receptor Activation; Registries; Research; Resources; Rice; Risk; Risk Factors; Role; Sampling; Sea; Serum; Signal Transduction; South Carolina; Structure; Testing; Therapeutic Intervention; Tissues; United States; Variant; Warburg Effect; base; cancer health disparity; cancer risk; cohort; diabetic; disease phenotype; glycation; glycosylation; inflammatory marker; innovation; mortality; non-diabetic; novel; prognostic; public health relevance; receptor; receptor binding; receptor for advanced glycation endproducts; sugar; therapeutic development; transcription factor; translational study; treatment strategy; tumor; tumor metabolism; tumor progression

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.

描述（由申请方提供）：糖化是糖与蛋白质、脂质和DNA的非酶促糖基化，导致产生称为晚期糖化终产物（AGE）的反应性代谢产物。糖基化发生时，过量的糖是可用的，并驱动许多与糖尿病相关的并发症。肿瘤的特征还在于高葡萄糖水平，其为用于能量产生的高速率糖酵解提供燃料（称为瓦尔堡效应）。Project SuGAR是一个基于社区的研究数据库，重点关注受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库存生物样本，探索在正常糖水平（非糖尿病海岛居民）和高糖水平（2型糖尿病海岛居民）的背景下，高AGE代谢物水平是否能预测癌症的发病率和死亡率。最近的研究已经导致我们的假设，即“AGE水平升高通过激活AGE-E2信号传导轴促进炎症而促进癌症差异”。本研究的具体目标1将分泌性AGE水平与患有和不患有2型糖尿病的SuGAR项目参与者的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群癌症发病率和死亡率以及癌症/糖尿病共病率的首次分析。AGEs通过作为晚期糖基化终产物受体（AGEs）的配体介导其许多有害作用。β-内酰胺酶是一种致癌的跨膜受体，可促进炎症反应。分泌型β-内酰胺酶（Secreted β-内酰胺酶，sNAR）是β-内酰胺酶的一种剪接变体，其可作为诱饵结构域受体来减少β-内酰胺酶的AGE细胞结合。较高的sRAGE水平与许多肿瘤类型的良好结果相关。具体目标2将测量与南卡罗来纳州的海岛人群中AGE水平和癌症发病率和死亡率相关的炎症标记物表达。了解糖尿病和癌症之间的生物学联系尤其受到缺乏潜在共同风险因素信息的困扰。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，我们将开发一种独特的资源，不仅可以解决这些混杂因素，还可以分析促进糖尿病，癌症和合并症的种族差异的特定因素。此外，AGE-炎症-信号传导轴可能作为预后/诊断标志物具有潜在的影响，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，可以在SuGAR项目和海岛社区内开发为临床试验。非裔美国人患糖尿病和癌症的风险增加，最终死亡。SuGAR项目资源的开发以及对糖基化在癌症中的作用的更深入了解有可能显著影响这一人群的生存和生活质量。