2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647916摘要：背景：血清中的 microRNAs (miR)具有重要臨床意義，尤其是miR-122 已被廣泛地應用在病毒性C 型肝炎的研究。miR-122 被發現可刺激C 型肝炎病毒（HCV）的複製。相對地，miR-122 在B 型肝炎（HBV）感染以及相關肝病的角色（目前被發現可抑制HBV 複製）只有一小部分是為人所知的。此外，基於miR-122 對HBV 和HCV 複製分別有不同的影響，血清中的miR-122 濃度對於B 型和C 型肝炎雙重感染的慢性肝炎患者的基本輪廓和臨床意義將是一個有趣的和重要的臨床問題，但至今尚未被研究過。另外，miR-122 可能與肝細胞癌的發生以及脂質代謝有密切相關。假設：為了釐清這些問題，我們首先假設miR-122 的表現與慢性病毒性肝炎的臨床表現有關，而且其相關性決定於肝病之病程和病因。具體地說，miR-122 的表現在慢性HBV 感染、慢性HCV 感染和雙重慢性HBV/ HCV 感染不同病因之間可能不同。第二，miR-122 的製造與釋放可能與HBsAg 製造有關，與HCV 共同感染有關。第三，我們假設miR-122 的濃度也許可以用做預測治療慢性B 型肝炎或雙重慢性B 型/C 型肝炎治療結果的生物標記。第四，我們假設miR-122 表現與血脂質代謝指標和肝癌的生成有關。目的：1. 檢查和比較 HBV 單一感染患者、HCV 單一感染患者和HBV/ HCV 雙重感染患者血清中的miR‐122 濃度的輪廓。2. 檢查血清的 miR‐122 濃度對自然病程和治療反應（以長效干擾素治療為主）的預測能力（精確度和靈敏度）3. 研究血清 miR‐122 濃度與HBsAg 製造，與HCV 共同感染的相關性。4. 研究 miR‐122 的濃度與血脂質代謝指標和肝細胞癌生成的相關性。研究方法：臨床部份，我們將前瞻性納入各種原因的肝炎病患，包括200 例HBV/ HCV 雙重感染患者、200 例HCV 單一感染患者和200 例HBV 單一感染患者。我們將分析血清miR-122 的濃度。此外，也會收集對照組，包含非B 非C 非酒精性脂肪肝病的患者（N =50），與血清ALT 正常的健康受試者（N=50）。血清中的miR-122 濃度將使用已認證的高靈敏度雜交測定法來定量。我們也將收集接受干擾素抗病毒治療患者的miR-122 的輪廓和演變過程，並且比較病例組和對照組的差異。實驗部份，我們將使用體外細胞培養模型來研究血清中的miR-122、B 肝表面抗原、HBV DNA 和HCV共同感染之間的相互作用。預期成果：我們將透過一個建立完善追蹤的族群，希望從中發現，HBV 單一感染患者和HBV/ HCV雙重感染患者循環中miR-122 濃度的輪廓其其臨床意義。我們也將釐清血清中miR-122 值作為生物標記來預測長效干擾素治療後的結果的應用價值；釐清血清中miR-122 濃度變化的機轉。<br> Abstract: Background: The clinical significance of serum microRNA (miR), particularly miR-122, hasbeen investigated extensively in viral hepatitis C. Specifically, miR-122 stimulateshepatitis C virus (HCV) replication. In contrast, the role of miR-122 in the hepatitis Bvirus (HBV) infection and related liver diseases has only been partly clarified (miR-122been found to suppress HBV replication). Based on these opposites effects, the profile andclinical significance of serum miR-122 in patients with dual chronic hepatitis B and C wouldbe an interesting and important clinical issue but not been investigated yet. Besides, thevalue of miR-122 as a biomarker for predicting clinical and treatment outcomes of chronicviral hepatitis was largely unknown. Furthermore, the clinical and virologic factorspotentially influencing the synthesis and release of miR-122 were not evaluated yet. Finally,miR-122 has been recently found to correlate with lipid metabolism and hepatocarcinogenesis.Hypothesis: To address these issues, we first hypothesize that the expression profile ofmiR-122 correlates with clinical phenotypes of chronic viral hepatitis, and are liverdisease stage- and etiology-dependent. Specifically, the expression profile of miR-122 maydiffer among chronic HBV infection, chronic HCV infection and dual chronic HBV/HCV infection.Second, we hypothesize that the synthesis and secretion of miR-122 are influenced by HBsAgsecretion and HCV coinfection. Third, we hypothesize that miR-122 level may be a usefulbiomarker for prediction of the treatment outcomes in patients with chronic hepatitis Bor dual chronic hepatitis B and C. Fourth, we hypothesize that miR-122 expression correlateswith lipid profile and the development of HCC.Specific aims:1. To examine and compare the profiles of serum miR-122 level in patients with HBVmonoinfection, HCV monoinfection, and dual HBV/HCV infection; and among patients atdifferent stage of liver disease2. To examine the predictive value (accuracy and sensitivity) of serum miR-122 indetermining the natural outcomes and treatment responses (peginterferon-based therapy)3. To investigate the mechanisms of miR-122 synthesis and secretion4. To investigate the correlations among miR-122, lipid profile and development of HCCPatients and Methods: 200 patients with HBV/HCV dual infection, 200 patients with HCVmonoinfection and 200 patients with HBV monoinfection will be prospectively enrolled. Inaddition, patients with non-B non-C nonalcoholic fatty liver disease (n=50) and healthysubjects with normal serum ALT (n=50) will be collected as controls. Serum miR-122 levelswill be quantified by using a sensitive hybridization-based assay. The profile and evolutionof miR-122 in patients receiving peginterferon-based anti-viral treatment will be collectedand compared among cases and controls. The interactions among serum miR-122, HBsAg, HBVDNA, and HCV coinfection will be investigated by using in vitro cell culture models.Expected Results: Taking advantage of a well established cohort, the profile and clinicalsignificance of circulating miR-122 in patients with HBV monoinfection and HBV/HCV dualinfection will be discovered. The value of serum miR-122 level as a biomarker to predictpost-peginterferon treatment outcomes will also be clarified. We will clarify the mechanismsaccounting for the level of circulating miR-122.B 型肝炎C 型肝炎雙重感染miR-122脂質代謝肝癌生成Hepatitis Bhepatitis Cdual infectionmiR-122lipid profilehepatocarcinogenesis