Drosophila NotchAxM1 mutant as CADASIL model to study rescuing effects by genetic modification and FDA-approved drugs

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题名:	Drosophila NotchAxM1 mutant as CADASIL model to study rescuing effects by genetic modification and FDA-approved drugs
作者:	游淳涵;Yu, Chun-Han
贡献者:	生命科學系
关键词:	遺傳性腦血管疾病;基因修飾;藥物篩選;果蠅;CADASIL;genetic modification;drug screening;Drosophila
日期:	2025-07-28
上传时间:	2025-10-17 11:25:12 (UTC+8)
出版者:	國立中央大學
摘要:	遺傳性腦血管疾病在臨床中相對罕見，但體顯性腦動脈血管病變合併皮質下腦梗塞及腦白質病變 (CADASIL) 作為其中最普遍的單基因小血管病，正逐漸受到關注。CADASIL是由NOTCH3基因突變所致，其特徵有反覆無常的缺血性中風、認知功能逐步退化及明顯的腦白質病變，從而大大增加了早期識別和採取適當治療的難度。由於目前CADASIL的治療多是以減緩不適症狀為主，本研究利用果蠅的氣管系統作為CADASIL模型，聚焦於基因修飾與藥物篩選來探討有潛力的且更加直接的治療策略。我針對Notch相關的基因進行修飾，發現過度表達neuralized (neur) 能部分挽救AxM1突變體幼蟲 (Notch EGF repeats發生半胱氨酸突變) 的氣管缺陷。此外，我與實驗室中的陳珮宜博士一起在FDA核准藥物庫中篩選出15種藥物能夠將AxM1突變幼蟲的時間延長至蛹期。後續實驗更是確認了其中兩種候選藥物在改善氣管分支缺損方面具備明顯效果。總之，本研究證實了AxM1果蠅氣管作為 CADASIL 模型的可行性，也驗證了基因修飾實驗與藥物篩選實驗在此模型中的有效性。期望本研究能促進 CADASIL 治療方式的發展，並朝向更具實質效果的治療選擇邁進。;Hereditary cerebrovascular diseases are relatively rare in clinical practice, but cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as the most common monogenic small-vessel disorder, has drawn increasing attention. CADASIL is caused by mutations in the NOTCH3 gene and is characterized by recurrent ischemic strokes, progressive cognitive decline, and prominent white matter lesions, all of which greatly complicate early diagnosis and effective treatment. Since current CADASIL therapies focus mainly on symptom relief, this study used the Drosophila tracheal system as a model to explore potential treatment strategies through gene modification and drug screening. I modified Notch-related genes and found that overexpressing neuralized (neur) can partially rescue the tracheal defects in AxM1 mutant larvae, which harbor a cysteine mutation in the Notch EGF repeats. In addition, collaborating with Dr. Pei-Yi Chen in the lab, we identified 15 compounds from the FDA-approved drug library that were able to extend the survival time of AxM1 mutant larvae. Follow-up experiments further confirmed that several of these candidate drugs had significant effects on improving tracheal branch defects. In summary, this work both confirms the feasibility of using the Drosophila trachea as a CADASIL model and demonstrates the effectiveness of separate gene modification and drug screening experiments in that model. We hope this study lays a foundation for developing more direct treatment options for CADASIL.
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