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（由申请人提供）：糖基化是用蛋白质，脂质和DNA糖的非酶糖基化，导致产生称为高级糖基化末端产物（年龄）的反应性代谢物。只要有过多的糖，就会发生糖化，并驱动与糖尿病有关的许多并发症。肿瘤还具有高葡萄糖水平的特征，该水平为能量产生的高速糖酵解（称为Warburg效应）。 Project Sugar是一个基于社区的研究数据库，专注于受2型糖尿病影响的海岛家庭。这项研究的目的是利用这种独特的资源及其银行的生物样品来探讨高年龄代谢物水平是否可以预测正常糖水平（非糖尿病海岛人）和高糖水平（2型糖尿病的Sea Islanders）的背景下的癌症的发病率和死亡率。最近的研究导致了我们的假设：“升高年龄水平通过激活年龄板信号轴促进癌症差异以促进炎症”。这项研究的特定目的1将分泌年龄水平与患有和没有2型糖尿病的糖参与者的癌症发病率和死亡率有关。这项最初的研究代表了南卡罗来纳州海岛人口中的癌症发病率和死亡率以及癌症/糖尿病的首次分析。年龄通过充当晚期糖基化终产物（RAGE）受体的配体来介导许多有害作用。愤怒是一种致癌跨膜受体，可促进炎症反应。分泌的愤怒（Srage）是一种愤怒的剪接变体，可以充当诱饵域受体，以减少愤怒的年龄细胞结合。在许多肿瘤类型中，较高的SRAGE水平与有利的结果有关。具体目标2将测量与年龄水平以及南卡罗来纳州海岛人口中的年龄水平以及癌症的发病率和死亡率有关的炎症标记表达。缺乏有关潜在的共享风险因素的信息，了解糖尿病与癌症之间的生物学联系特别困惑。通过开发项目糖中包含的现有数据集以包括癌症的发病率和死亡率，我们将开发一种独特的资源，不仅可以解决这些混杂因素，还可以分析两种疾病的糖尿病，癌症和合并症的种族特定因素。此外，年龄射流炎症信号传导轴可能会作为预后/诊断标记物具有潜在影响，以指导侵袭性疾病的治疗策略。它还可以定义一个新型的治疗干预领域，该领域可以作为糖和Sea Island社区中的临床试验开发。非洲裔美国人增加了发展的风险，并最终死于糖尿病和癌症。项目糖资源的发展以及对糖化在癌症中的作用的进一步了解有可能显着影响该人群中的生存和生活质量。