腸炎小鼠模式：Fzd7基因剔除小鼠之表現型與機制分析

Colitis mouse model: Phenotypic and mechanistic analysis of Fzd7 deletion in mice

古乃心(Nai-Xin Gu)

指導教授 ： 何元順

共同指導教授 ： 陳怡帆(Yi-Fan Chen)

臺北醫學大學/醫學院/醫學科學研究所/碩士(2019年)

摘要

Fzd7基因所轉譯出的Fzd7蛋白 (Frizzled7 receptor) 為 Wnt/Fzd7訊息傳導路徑 (Wnt signaling pathway) 中重要的訊息接收者。目前研究發現，Wnt/Fzd7訊息傳導路徑的下游目標基因會參與腸道幹細胞的調控，影響腸道幹細胞的分化與增生。此外，腸道上皮細胞屬於更新快速的細胞，需要腸道幹細胞不斷進行分化以維持上皮細胞恆定。因此，我們推測當 Fzd7 基因缺失時，將影響腸道幹細胞的運作機制，而導致分化後的腸道上皮層的細胞產生型態或功能上的異常。
在本篇論文中，我們假設在Fzd7基因缺失的情形下會影響腸道幹細胞的功能，並對於小鼠之生理功能造成影響。根據假說，首先建構了Fzd7基因剔除小鼠並對其進行全身性觀察，發現Fzd7基因剔除小鼠的某些器官，如心肌、腎臟、脾臟、小腸等有不正常的型態。再進一步觀察後發現，Fzd7基因的缺失會造成小鼠的腸道長度變短以及腸道內之杯狀細胞數量明顯下降，進而影響其功能，使其所分泌之黏液 (mucus) 減少進而導致腸道黏膜屏障 (intestinal mucosal barrier) 的功能被破壞，最終產生腸道發炎 (colitis) 反應。另外，我們也使用DSS來加劇腸道發炎的現象，結果發現基因缺失與化學品的加乘作用，會使的腸道發炎更嚴重。我們期望可以藉由這個動物模式來研究Fzd7在腸道發育以及腸道再生這些部分所扮演的功能;另外，也期望相關的研究可有助於醫療或藥物研發，未來應用在臨床病人上。

關鍵字

腸炎 ； Fzd7基因 ； 基因剔除小鼠 ； 腸道上皮 ； 發炎反應 ； 癌症發生

並列摘要

Frizzled7 (Fzd7) receptor is the important signaling receptor in the Wnt signaling pathway. The purpose of Fzd7 receptor is to receive Wnt signaling molecular and to activate beta-catenin for the downstream pathway processing the transcription of the target genes. Currently, the research had indicated that these target genes involved in regulating the proliferation and differentiation of intestinal stem cells (ISCs). Intestinal epithelial cells are considered to be rapid-renewing cells, and intestinal stem cells keep differentiating to maintain the homeostasis of intestinal epithelial cells. Therefore, it is predicted that the function of intestinal stem cells will be affected when Fzd7 gene undergoes deletion.
In this study, we hypothesize the Fzd7 deficiency causes the defect on intestinal e specific aims as follow, (1) to establish and characterize the Fzd7 gene knockout mouse model, especially focus on intestine tract; (2) to analyze the effect of Fzd7 deletion on regeneration/repair in intestine; (3) to verify the mechanisms of Fzd7 in regulating the proliferation and differentiation of intestinal stem cells and colitis formation.
It can be seen from the results that the deletion of the gene of Fzd7 affects the expression of goblet cells and causes functional defects, resulting in reduced secretion of mucus and destroyed the intestinal mucosal barrier, finally triggering an inflammatory response. We expect this animal model can facilitate to understand the functions of Fzd7 on intestine development and regeneration, and furthermore explore therapeutic for human patients with colitis.

並列關鍵字

Enterocolitis ； Fzd7 ； knockout mice ； intestinal epithelium ； inflammation ； tumorigenesis

參考文獻

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