臺灣博碩士論文加值系統

老化在生物體中是一種複雜且多因子誘發的過程。先前的研究在不同物種中發現有許多老化與長壽相關的基因被發現，由於這些基因的發現，提供了抗老化醫學的可能治療標的。然而，調控抗老化與長壽基因表現的分子機轉尚未完全釐清，仍須進一步探討。近期的研究發現，一個主要在腎臟表現被命名為可羅素(klotho)的抗老化基因，其過量表達的基因轉殖鼠其壽命比野生型老鼠長。然而，可羅素的調節機轉目前仍待研究，因此本論文的研究主要是探討抗老化荷爾蒙及天然多酚白藜蘆醇對可羅素基因在動物與細胞中表現的分子調節機轉。
臨床上發現荷爾蒙代療法可以改善許多老化相關的症狀，並且在年老的男性血液中雄性激素的含量與壽命長短具有正向關連性。因此，論文的第一部份是探討雄性激素對可羅素基因表現的分子調節機轉。小鼠腎臟細胞在雄性激素刺激後可以藉由雄性激素受器結合至可羅素基因啟動子上的雄性激素受器結合區進而促進可羅素基因的表現。
白藜蘆醇在葡萄皮與紅酒中具有很高的含量，先前研究證實它具有抗氧化及抗癌等功效。因此，本論文第二部份將探討植物性荷爾蒙白藜蘆醇對可羅素基因表現的分子調節機轉。在白藜蘆醇刺激的小鼠與腎臟細胞中可以觀察到activating transcription factor 3 (ATF3) 及 c-Jun在細胞核內表現量增加並且互相作用形成聚合體結合至可羅素基因啟動子上的ATF3與c-Jun結合區促進可羅素基因增加表現。
綜合以上的結果推論雄性激素與白藜蘆醇的抗老化作用，可能是透過刺激腎臟抗老化基因可羅素的表現。因此，在未來將可做為治療如老化或慢性腎臟病所導致可羅素基因表現量降低之疾病的可能性，另可利用參與其分子調控機轉之相關基因作為抗老化治療的研究標的。而未來研究方面可以利用人類可羅素起動子報告系統在細胞模式中進行抗老化藥物的篩選，並找出更具專一的分子調節機轉。

Ageing is a complex and multifactorial process in multicellular organisms. Many studies have proposed genetic theories of ageing and numerous genes related to ageing and longevity that have been identified from diverse organisms, revealing potential targets for anti-ageing strategies. The klotho gene, predominantly expressed in the kidney, has recently been discovered to be an ageing suppressor gene and transgenic mice overexpressing the klotho protein survive longer than their normal littermates. However the molecular mechanism involved in regulating regulation of renal Klotho gene expressions remains largely unclear. Hormone replacement therapy (HRT) has been identified to prevent and reserve the ageing associated disease and several studies have demonstrated a relationship between testosterone level and life span in elderly men. In first part of this dissertation, we investigated the regulatory effects of anti-aging hormone testosterone on renal klotho gene expression in vivo and in vitro. In testosterone-administered mouse kidney and NRK-52E cells, increased klotho expression was accompanied by the upregulation of the nuclear androgen receptor (AR). Overexpression of AR enhanced the expressions of the klotho mRNA and protein. Conversely, testosterone-induced klotho expression was attenuated in the presence of flutamide, an AR antagonist. A reporter assay and a chromatin immunoprecipitation assay demonstrated that AR directly binds to the klotho promoter via androgen response elements (AREs), which is reconfirmed its importance for AR binding via the element mutation.
Resveratrol is a natural polyphenol primarily found in grapes and red wine that offers various benefits for common age-related diseases because of its anti-ageing and antioxidant properties. However, whether resveratrol plays a role in the regulation of renal Klotho expression has not been studied yet. In second part, we determined that resveratrol, a natural phytoestrogen, induced renal Klotho expression both in vivo and in vitro. In the mouse kidney, resveratrol administration markedly increased both Klotho mRNA and protein expression. In resveratrol-treated NRK-52E cells, increased Klotho expression was accompanied by the upregulation and nuclear translocation of activating transcription factor 3 (ATF3) and c-Jun. ATF3 or c-Jun overexpression enhanced the transcriptional activation of Klotho. Conversely, resveratrol-induced Klotho expression was attenuated in the presence of dominant-negative ATF3 or c-Jun. Coimmunoprecipitation and a chromatin immunoprecipitation assay revealed that ATF3 physically interacted with c-Jun and the ATF3/c-Jun complex directly bound to the Klotho promoter through ATF3- and AP-1-binding elements. c-Jun cotransfection augmented the effects of ATF3 on Klotho transcription in vitro.
In summary, both testosterone and resveratrol administration enhance the renal expression of the anti-ageing Klotho gene in vivo and in vitro. A testosterone supplement might have the potential to extend the life span by recruiting AR onto the AREs of the klotho promoter. The transcriptional factors ATF3 and c-Jun functionally interact and coordinately regulate the resveratrol-mediated transcriptional activation of Klotho. In the future work, to establish a stab human renal cell line containing klotho promoter driving luciferase expression vector for high-throughput screening of anti-ageing drugs.

List of Figures -------------------------------------------------------------------------------------III
List of Tables ----------------------------------------------------------------------------------------V
中文摘要-----------------------------------------------------------------------------------------------VI
Abstract--------------------------------------------------------------------------------------------VIII
Abbreviations ----------------------------------------------------------------------------------------XI
Chapter 1
General introduction----------------------------------------------------------------------------------1
Chapter 2
Material and methods----------------------------------------------------------------------------------14
Chapter 3
The molecular regulation of anti-aging klotho expression by testosterone------------------------------25
Chapter 4
The molecular regulation of anti-aging klotho expression by resveratrol-------------------------------48
Chapter 5
Discussion--------------------------------------------------------------------------------------------68
Chapter 6
Conclusion and future perspectives--------------------------------------------------------------------78
Chapter 7
Reference---------------------------------------------------------------------------------------------80

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