錯誤折疊以及聚集的蛋白質累積被認為是造成神經退化性疾病的成因之一，當這些損壞的蛋白質持續與其他的氧化物質結合成溶酶體無法分解的顆粒，將會對細胞是有害的，這些隨時間而不斷增長的顆粒稱為脂褐素，通常含有脂質、蛋白質及微量金屬。因此研究脂褐素對神經退化性疾病的影響以及可能的治療手段是許多研究單位積極努力的目標。然而，在高等動物中觀察脂褐素是一件困難的事情，因此，我們選用秀麗隱桿線蟲做為動物模型，因其具有豐富的生物學訊息以及穩定的基因型態，適合利用於基因學、遺傳學的探討。
已知熱休克蛋白主要作用在於清除以及修復錯誤摺疊的蛋白，因此本研究發展一種可定址式及快速升溫的光電裝置來誘發熱休克蛋白，藉以協助清除過量之脂褐素，進而治療脂褐素造成的退化現象。研究中主要採用野生株線蟲(N2)、及轉基因線蟲SJ4005(HSP-4::GFP)和CL2070(HSP-16.2::GFP)。實驗條件有熱休克蛋白誘發、抗憂鬱藥物奧氮平(Olanzapine)使脂褐素堆積增加、利用RNA 干擾技術抑制線蟲的熱休克蛋白表達以及觀察脂褐素堆積增加狀態下氧化壓力的高低。結果顯現出光電裝置誘發熱休克蛋白後的線蟲其累積的脂褐素濃度確實明顯下降，也延長了線蟲壽命，然而這樣的刺激也造成線蟲產卵數的下降。餵食副作用為脂肪增生的抗憂鬱藥物奧氮平間接提升線蟲體內的脂褐素濃度，造成線蟲壽命以及產卵數目的短少。進一步探討熱休克蛋白對於清除脂褐素顆粒的重要性，利用RNA 干擾技術抑制線蟲的熱休克蛋白表達，由結果得知熱休克蛋白的表達抑制會造成線蟲的脂褐素濃度增加、壽命減短及產卵數目大幅減少的情況。有一假設氧化壓力是造成脂褐素大幅增加的主因，實驗中藉於餵食線蟲不同次數的奧氮平來探討氧化壓力及脂褐素之間的關係，結果證明兩者為正相關。
未來我們的研究將與帶有阿茲海默症基因的線蟲做連結，藉由施加光電裝置誘發熱休克蛋白對脂褐素作用，期望可以改善線蟲體內脂褐素濃度、增長壽命及改善線蟲游動步態缺陷的情況。最終成果預期可以對未來老化相關疾病治療有顯著的貢獻。

The accumulation of misfolded or aggregated proteins in aging animals has been considered one of the causes of neurodegenerative diseases. When the damaged proteins further aggregate with other waste materials, such as lipid and metals, they will form a complex which is well known as Lipofuscin (LF). LF is usually considered a cytotoxic material due to highly oxidative stress. However, it remains difficulty to observe the LF granules in live animals to date due to the limitation of the current technology. As a result, Caenorhabditis (C.) elegans is used as a model animal in this thesis. C. elegans has been widely used as a model organism for fundamental biological research due to its potential in developmental biology, genetics and neuroscience.
It is known that HSPs can function as molecular chaperones as well as “dustmen” in cells. In this research, we developed a novel addressable heating technique based on an optoelectric device to induce heat shock proteins (HSPs) to scavenge the LF granules. Heat shock response is a protective mechanism typically induced by heat that helps animals to survive in harsh environments. In the thesis, the wild-type worms (N2) and the transgenic worms SJ4005 (HSP-4::GFP) and CL2070 (HSP-16.2::GFP) were investigated. The experimental conditions included induction of HSPs, LF accumulation of feeding olanzapine, which is an antipsychotic drug but has a side effect on lipid-increasing, suppressing the expression of HSPs by RNAi technique and oxidative stress measurement. The results showed that induction of HSPs decreased LF accumulation and the number of progeny, but extended lifespan of worms. Meanwhile, exploring the effects of LF on aging, feeding olanzapine caused the increase of LF accumulation, yet the decreases of lifespan and progeny. Furthermore, suppressing the expression of HSPs by RNAi technique proves the importance of the LF removal. Applying to optoelectric or olanzapine treatment compares the results of LF accumulation, lifespan and numbers of progeny. The results showed that inhibiting HSPs makes LF accumulation increase, lifespan decrease, and progeny decline. Besides, the hypothesis of increasing LF is oxidative stress raised. The result shows that there is a positive correlation between the LF accumulation and ROS.
In the future, optoelectric treatment will be applied for Alzheimer’s worms. We hope that inducing HSPs could decrease LF accumulation, extend lifespan and improve the swimming gait. As last, the success of the results may provide a potential impact to the active treatments in age-related diseases.

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