模式生物斑馬魚在人類疾病研究上的重要性，在近十年來逐漸被重視，已被使用來誘發許多感染性或發炎性疾病，以瞭解疾病的產生機制，其中包含細菌或是病毒所引起的感染，自體免疫腦脊髓炎以及大腸炎，有些疾病模式更被利用來測試新穎化合物的治療效果，除此之外，更有研究團隊著力於開發斑馬魚自動化影像分析藥物測試平台。進一步整合疾病模式以及藥物篩選平台，將加速藥物研發的過程，並且改進現今藥物開發的方法。
在這部論文的第一部分，將提及由我們首先建立的斑馬魚真菌感染模式，用以瞭解白色念珠菌(Candida albicans)的致病機制，尤其是菌絲生長。藉著組織學和存活率分析，我們發現白色念珠菌能在魚體中的各個器官上，形成菌落，並且感染斑馬魚，而這樣的感染與否和打入的菌數是有關連的，同時我們也在以白色念珠菌來感染幼魚，並且觀察到免疫細胞和菌交互作用時的即時活體影像，兼以基因表現分析，我們檢測出病原體在過程中，大量表現致病基因，宿主在反應感染時，啓動促進免疫系統和清除病原的基因表現，更進一步使用許多白色念珠菌變異株感染斑馬魚，發現斑馬魚也能用來鑒別不同感染能力的菌株，之後並使用微陣列分析，來觀察時間序列中，真菌病原和斑馬魚宿主分別的基因群表現特徵，期望用於系統生物學之方法分析，來瞭解兩者在感染過程中，有哪些重要且未知的基因參與其中，並且希望發掘新的藥物開發目標，以對抗真菌所造成日益嚴重的醫療問題。
在第二部分，敘述如何將斑馬魚幼魚浸泡在含有一種化學物質(2,4,6-trinitrobenzenesulfonic acid)的溶液，以誘發發炎性腸症(inflammatory bowel disease)，並且改進前人的實驗步驟，用於挑選具免疫調節功能的分子。利用觀察腸道病變和檢測基因表現，我們從選定的色氨酸代謝產物(tryptophan metabolites)中，挑選出具有活化芳香烴受體(aryl hydrocarbon receptor)，並且能保護魚體免於腸症之分子。其中挑選出的硫酸吲哚酚(Indoxyl sulfate)，原先是被認為是一種造成尿毒症的毒素，但我們的研究卻指出這種毒素俱有生理功能，發現其具有免疫調節的作用，以誘發細胞激素22 (interleukin 22)來保護幼魚免於發炎性腸症的侵襲。
總結來說，我們延伸了斑馬魚的使用，用以了解真菌感染之機制，並且提供一個簡化的篩藥流程，來挑選具免疫調節以避免腸道過度發炎的化學物質，加上自動化機器平台的使用，期望能在了解真菌感染和炎症產生過程有大進展，增進新穎治療方法的研發，以消弭病人的痛苦。

The zebrafish model has become one of the best research systems for high throughput drug screening. The importance of zebrafish model in human disease research and for drug discovery and development is well-recognized in the past decade. To understand the pathogenesis of infectious and inflammatory diseases, many zebrafish disease models were established, including bacterial or viral infection diseases, autoimmune encephalomyelitis and colitis. Some of the models have been applied for drug screening to evaluate the therapeutic effect of novel compounds. Besides, the zebrafish model can be integrated with image-based assays, which can transform into an automated drug-evaluating platform. Such integration of disease model and screening platform can greatly advance our understanding of immunity-related pathogenesis and to improve the drug development.
By applying histological, gene expression and survival assays, we are the first group to establish a fungal infection model with zebrafish to investigate Candida albicans’ virulence, especially its hyphal formation during infection. We demonstrated that C. albicans could colonize and invade zebrafish at multiple anatomical sites and kill the fish in a dose-dependent manner. Moreover, using zebrafish embryos, we monitored C. albicans infection and visualized the interaction between pathogen and host myelomonocytic cells in vivo. Inside zebrafish, we observed the progression of the C. albicans yeast-to-hypha transition by tracking morphogenesis, and we monitored the corresponding genes expression of the pathogen. We then performed time-lapse microarray study to analyze the genes expression patterns in fungal pathogen and zebrafish host simultaneously for systems biology approach analysis, which the abovementioned is the first part of this thesis.
There are two parts in my thesis and the second part is to present how we modified a published protocol to induce inflammatory bowel diseases (IBD) in zebrafish larva by incubating fish in 2,4,6-trinitrobenzenesulfonic acid (TNBS) contained solution and apply the protocol for drug screening to select immunomodulatory molecules. By incorporating IBD scoring system and genes expression assays, we selected effective candidates from tryptophan metabolites in the activation of aryl hydrocarbon receptor (AhR) signaling to protect fish from IBD and we found the uremic toxic, indoxyl sulfate (IS), possess a physiological function to promote the expression of interleukin 22 to protect fish gut from IBD instead to damaging the physiological homeostasis. This finding proposed the IS can play a role to maintain the immunological balance, which is other than what had been reported as a toxic molecules.
In conclusion, our findings have expanded the application of zebrafish model to study fungal infection. We also proposed a straightforward way to evaluate novel immunomodulation chemicals for their effects in controlling inflammation in gut. With application of automated robotic platform, we expect to make significant progress in understanding pathogenesis of more infectious and inflammatory diseases, and to develop novel therapy for related patients.

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