Dr. Chang, Zee-Fen's Laboratory

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國立臺灣大學醫學院
分子醫學研究所張智芬老師實驗室
Ph.D. Chang, Zee-Fen
 
Institute of Molecular Medicine, School of Medicine, National Taiwan University, 7 Chung Shan South Rd., Taipei, Taiwan, R.O.C.
Tel: 886-2-23123456 ext. 88590(office), 88591(Lab)
Email: zfchang@ntu.edu.tw
 
 

Research Interest

去氧核醣核酸新陳代謝與基因體的穩定性
核苷酸是生命體之基本架構單位,其生成,分解,修飾均影響 細胞核及粒腺体基因体品質,我們基因體的DNA,因遭受內源性及外源性的毒物作用,經常形成損傷,藉由移除損傷DNA及正確核苷酸之嵌入,這些修復影響我們的健康與疾病。我的實驗室著重研究正常與癌細胞內,核苷酸質與量之供給和DNA〝錯誤修復〞之關係,進而希望藉此發展疾病治療與預防之分子策略。

核苷酸合成之特定位置
核苷酸之新陳代謝主要發生在細胞質,在人類細胞內 rNTP/dNTP 之比值超過100,最近在酵母菌之研究,已揭露rNTP在DNA複製過程會被嵌入DNA,造成基因損傷,這引發了一個有趣的問題,是否dNTP合成需要即時匯集於DNA損傷區,才能有效的準確修復DNA,而其機制為何?

粒腺體與核苷酸品質
粒腺體是細胞中產生氧化壓力之主要胞器,在我的研究結果中顯示,正常與癌細胞粒腺體之差異性與核苷酸之品質,有密不可分之關係。目前,我們正在探討粒腺體動態控制與自噬過程,對正常與癌細胞內核苷酸品質之分子調節機制。

治療契機之發展
核苷酸之合成分解及粒腺體功能,在正常及癌細胞內有極大差異性,我的實驗室過去已發展出抑制TDP形成之小分子,我們希望藉著對DNA損傷及修復和粒腺體反應機制之理解,發展針對癌細胞具選擇性毒殺作用之組合性治療策略。

In one’s life time, DNA lesions in the genome are constantly generated due to endogenous and exogenous exposure to genotoxic chemicals from all sources. Repair of these DNA damages that require nucleotide incorporation has the consequent impact on health and disease. We are interested in how nucleotide supply affects DNA repair in normal and cancer cells. Understanding the process leads to DNA “mis-repair” resulting from deficiencies in quality and quantity of nucleotides will be useful for developing therapeutic and prevention strategies against diseases.

Site-specific synthesis of nucleotide
It is known that nucleotide metabolism mainly takes place in the cytoplasm. The ratio of rNTP/dNTP is more than 100 fold. Recent yeast studies have shown rNTP mis-incorporation in DNA replication. This evokes one major question if dNTP synthesis at DNA damage sites offers advantage to increase local dNTP for correct DNA repair. We investigate the mechanism of chromatin remodeling proteins in the recruitment of dNTP synthesis enzymes at damage sites for DNA repair.

Mitochondria in nucleotide quality control
Mitochondria are the major source of oxidative stress in our cells. Normal and cancer cells are different in the quality control of mitochondria. My laboratory has found that this difference plays a determining role in the quality of nucleotide supply in DNA repair. The mechanisms including autophagy and mitochondrial fusion/fission contributing to nucleotide quality control in cancer and normal cells are under investigation.

Developing the therapeutic strategy
In response to DNA damage, both nucleotide synthesis and mitochondrial dynamics are differently regulated in normal and cancer cells. We have developed small molecules that inhibit the step of dTMP to dTDP. In combination with genotoxic chemical and autophagy blockers, we are establishing new therapeutic cocktails that are selectively toxic to cancer cells according to the molecular context of tumor.

 

 

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