以客觀存在之腎臟損害和功能異常的臨床表現為診斷依據的腎臟疾病，業已成為全世界所共同面臨的危害人類健康的一項主要健康問題。現今，人群中有超過十分之一的人患有慢性腎臟疾病（CKD）, 該病的患病率不亞於糖尿病 (James et al., 2010)。慢性腎髒病是一種難以治癒的疾病。儘管存在有效的治療方法，但在全世界範圍內，慢性腎髒病仍舊是導致終末期腎臟疾病和死亡的首要原因。據2010年全球疾病負擔的研究報導 (Lozano et al., 2013)，在引起全球死亡總數原因列表中，慢性腎髒病由1990年的第27位（年齡標準化的每100 000人的年死亡率為15.7）躍升至2010年的第18位（每100 000人的年死亡率為16.3）。慢性腎髒病的攀升趨勢僅次於HIV和AIDS。這種狀況已經引起高度關注，應對措施的實施刻不容緩！因此，迫切需要慢性腎髒病早期診斷和治療的有效方案。 / 纖維化是慢性腎髒病這一以終末期腎髒病（ESRD）為結局的疾病腎臟損傷和進展的主要病理特徵。現已確立转化生长因子β/Smads 信号蛋白（TGF-β/Smad）在腎臟纖維化發病機制中具有主要的作用。在過去近20年對於转化生长因子β/Smads 信号蛋白在慢性腎髒病發病機制中的作用研究揭示：Smad3在腎臟纖維化中起致病作用，而Smad2和Smad7具保護作用。鑒於转化生长因子β/Smads 信号蛋白在免疫調節中也發揮關鍵作用，直接針對转化生长因子β/Smads 信号蛋白的干預方案可能引起免疫損傷的副作用。因而，針對转化生长因子β/Smads 信号蛋白特異性下游靶目標的療法是對抗慢性腎髒病更好的選擇。 / 自首個微小核糖核酸的發現至今，已歷經20年。微小核糖核酸在基因表达的转录后起著重要調節作用。現已明確，在人類疾病包括腎臟病的發生和/或進展中存在微小核糖核酸的表達或功能的失調。最近的研究明確的表明，微小核糖核酸與腎臟疾病的發病機制密切相關。另外，已有確鑿的證據顯示，一些微小核糖核酸正是转化生长因子β/Smads信号蛋白的特異性下游。並且我們發現，不僅在转化生长因子β和血管緊張素II誘導的體外纖維化反應中，而且在小鼠體內梗阻性和高血壓性腎病模型中，微小核糖核酸-433-Azin1軸不但在腎臟纖維化中起重要作用，並且和转化生长因子β/Smad3信号蛋白密切相關。據重要意義的是，藉助安全、有效的超聲微泡介導的基因轉染方法，通過逆轉失調的微小核糖核酸-433-Azin1軸，有效的抑制了小鼠腎臟疾病的進展、腎組織的損傷并減少了蛋白尿的排泄。因此，微小核糖核酸-433-Azin1軸不但可以作為慢性腎臟病早期診斷的生物學標記，也能夠成為遏制甚至逆轉慢性腎髒病的治療靶點。 / 近年來，從基礎到臨床旨在預防和治療慢性腎髒病的研究已取得碩果累累。基於以转化生长因子β/Smad3信号蛋白特異性微小核糖核酸為把目標的治療策略，預見了遏制慢性腎髒病治療的未來希望。然而， 消除慢性腎髒病這一世界性的人類健康威脅，仍需付諸長期不懈的努力。 / Kidney disease is diagnosed with objective clinic manifestation of kidney damage and renal dysfunction has been recognized as a major global health burden. Nowadays, more than one out of ten people have chronic kidney disease (CKD) and the overall prevalence is not less than that of diabetes (James et al., 2010). CKD is a kind of persistent ailment. In spite of the availability of medical treatments, CKD continues to be a leading cause of end stage of renal disease (ESRD) and death worldwide. Reported in the 2010 Global Burden of Disease study (Lozano et al., 2013), CKD was ranked from 27th in 1990 (age-standardised annual death rate of 15.7 per 100 000) and rose to 18th in 2010 (annual death rate 16.3 per 100 000) in the list of causes of total number of global deaths. The growing momentum of CKD was just second to that for HIV and AIDS. This situation has claimed our serious attention and the prompt action is imperative. Thus, effective early diagnosis biomarker and treatment of CKD are urgent needed. / Fibrosis is the key feature during renal lesion formation and progression in CKD which will be ended in ESRD eventually. It has been established that Transforming growth factor β/Combination of the Drosophila protein "Mothers against decapentaplegic" (MAD) and C. elegant protein SMA (TGF-β/Smad) signaling plays a central role in the pathogenesis of renal fibrosis. For last two decades, dissection of the critical role of TGF-β/Smad signaling in the fibrogenesis of CKD has unveiled that Smad3 plays a pathogenic but Smad2 and Smad7 play a protective role in renal fibrosis. As TGF-β/Smad signaling also plays a crucial function in immunity, targeting TGF-β/Smad signaling may cause adverse effect. Thus, targeting specific downstream of T GF-β/Smad signaling should be a better alternative to fight against CKD. / A score of years has elapsed from the first microRNA discovery. MicroRNAs are important post-transcriptional regulators of gene expression. It is now widely acknowledged that the dysregulation of microRNA expression or action underlies the onset and/or development of various human diseases including kidney disease. Recently, researches have substantial evidences that microRNAs are tightly associated with the pathogenesis of kidney disease. In addition, eye-catching tangible evidences showed that several microRNAs are specific downstream of TGF-β/Smad3 signaling. Moreover, we found that not only in TGF-β and angiotensin II induced fibrotic response in vitro, but also in mouse models of obstructive and hypertensive nephropathy, microRNA-433-Azin1 axis is vital in renal fibrosis and is closely related with TGF-β/Smad3 signaling. Last but not least, our study suggests that, using a safe, effective, ultrasound microbubble-mediated gene transfer therapeutic method can significantly halt the progression of kidney lesions and reduce renal tissue damage and the excretion of albuminuria by balancing the microRNA-433-Azin1 axis. Hence, microRNA-433-Azin1 axis may act either as biomarkers favorable early diagnosis or therapeutic targets to halt or even reverse CKD. / The bench and bedside research on preventing and managing CKD have gained fruitful results in recent decades. Therapeutic strategy against TGF-β/Smad3 specific microRNA brings us a bright future in combating against CKD. However, more endeavors are necessary to eliminate the enormous burden of CKD worldwide. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Rong. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 182-202). / Abstracts also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_1202917 |
| Date | January 2014 |
| Contributors | Li, Rong (author.), Chung, Chi Kong (thesis advisor.), Chinese University of Hong Kong Graduate School. Division of Chemical Pathology. (degree granting institution.) |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, bibliography, text |
| Format | electronic resource, electronic resource, remote, 1 online resource (xx, 202 leaves) : illustrations (some color), computer, online resource |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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