2014-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646233摘要：本計劃希望藉由臨床醫師與基礎醫學研究者共同合作，以最新的代謝體分析與生物信息學達成下列目標: (1)找出胰臟癌引發之糖尿病的代謝體特徵; (2)發現胰臟癌分泌的致糖尿病因子及可早期偵測胰臟癌的生物標記; (3)臨床實際驗證所發現的生物標記之效力。 由於早期少有症狀，85％的胰臟癌發現時已屬末期，因此急需能早期偵測的方法。40％的患者在發現胰臟癌之前兩年內發生糖尿病(胰臟癌之新發生糖尿病)，是一可在症狀發生前18~24個月提早發現的線索。此糖尿病是由於胰臟癌分泌未知的致糖尿病因子所引起，瞭解其背後的代謝異常有助於發現未知的致糖尿病因子及可早期偵測胰臟癌的生物標記。代謝體分析可全面性的檢視生物體的代謝，是研究此問題的理想工具。 本計劃將於3年期間進行3項連續性研究: (1)比較有、無新發生糖尿病之胰臟癌及一般糖尿病患者血漿的代謝體，找出胰臟癌新發生糖尿病的代謝體特徵; (2)以生物信息學分析各種代謝物與腫瘤特色及胰島素分泌/胰島素阻抗之相關性，尋找可能的生物標記及致糖尿病因子; (3)檢測新生物標記鑑別胰臟癌與非胰臟癌(糖尿病、慢性胰臟炎、健康人)的能力。能早期偵測胰臟癌的生物標記可望降低胰臟癌的高死亡率，而找出致糖尿病因子將有助於發現新治療標的。<br> Abstract: Through collaboration between clinicians and basic scientists, this project aims to discover novel biomarkers for early detection of pancreatic cancer (PC) using high-throughput metabolomics and bioinformatics platforms. PC is the most lethal cancer. Surgical resection of tumor is the only potential cure, but early PC rarely causes symptoms and 85% of the tumors are already unresectable at diagnosis, underscoring the urgent need for novel strategies to enable early detection. PC associated new-onset diabetes, which occurs in approximately 40% of PC patients within 2 years before the tumor is diagnosed, provides a potential opportunity to detect PC 18 to 24 months before onset of symptoms, when the tumor is generally resectable. Notably, new-onset diabetes resolves or significantly improves after tumor resection, supporting that it is mediated by unknown tumor-secreted diabetogenic factors. Understanding the metabolic alterations underlying PC associated new-onset diabetes may lead to discovery of the diabetogenic factors and novel biomarkers for early diagnosis of PC. Through systematic investigation of the complete set of metabolites of an organism, metabolomics is an ideal tool to decipher the metabolic alterations underlying PC associated new-onset diabetes. Using the latest metabolomics and bioinformatics platforms, this project aims to: (1) identify the metabolomic signature of PC associated new-onset diabetes; (2) discover potential biomarkers and the diabetogenic factors; (3) validate the clinical usefulness of the discovered biomarkers. To achieve those aims, three interrelated consecutive studies will be conducted over 3 years: (1) metabolomic signature identification: plasma samples from patients of PC with new-onset diabetes, PC without diabetes, and diabetes without PC are analyzed by gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS). The metabolomic profiles of those 3 groups of patients are compared using pattern recognition and molecular identification to identify the metabolic signature of PC associated new-onset diabetes. (2) Discovery of biomarkers/diabetogenic factors: the levels of individual metabolites in the metabolomic signature are correlated with tumor stage, indexes of insulin secretion and resistance, and patient survival. In patients who receive tumor resection, the levels of metabolites after surgery are further analyzed and compared with those before surgery to identify those that correlated most with resolution/improvement of diabetes after tumor resection. All data are then integrated using bioinformatics tools including mass spectrum, network, and modeling analysis to identify potential biomarkers and diabetogenic factors. (3) Biomarker validation: the levels of the potential biomarkers are measured among patients of PC, chronic pancreatitis (CP), diabetes, and normal healthy controls to analyze the sensitivity and specificity of the biomarkers for differentiating PC from non-PC (CP, diabetes, and normal), and to identify the best combination of biomarkers for various clinical scenarios. If our aims are achieved, novel biomarkers for early detection of PC may improve the grave prognosis of PC, and identifying the diabetogenic factors may yield novel therapeutic targets.Research Participantsthe League of Universities in Northern Taiwan for Human Research Protection Programthe ethical principles in social and behavioral sciences researches