Dr. Wang, Guey-Shin ’s Lab王桂馨 博士 實驗室

RESEARCH

The laboratory is interested in the mechanism of cardiac and neural pathogenesis in myotonic dystrophy type 1 (DM1). DM1 is the most common form of adult-onset muscular dystrophy, is dominantly inherited and affects multiple tissues with symptoms including myotonia, muscle wasting, cataract, conduction defect, cardiomyopathy, daytime somnolence and psychiatric disorders. DM1 is caused by a CTG trinucleotide expansion in the 3』 untranslated region of the DMPK gene. DMPK mRNA containing CUG repeats accumulates in nuclear foci and affect nuclear and cytoplasmic activities of RNA binding proteins such as muscleblind like 1 (MBNL1) and CUGBP1 and ETR-3 like factor (CELF) proteins. The resulting sequestration of MBNL1 and PKC-mediated up-regulation of CELF1 cause the mis-regulated alternative splicing, translation and mRNA stability. Cardiovascular disease is the second most common cause of death in individuals with DM1 accounting for ~30% of fatalities. The occurrence of cognitive and behavioral impairment in individuals with DM1 is high. However, the mechanisms of causing the cardiac and neural deficits are remained unknown. We have established mouse models for investigating how cardiac and neural phenotypes are developed. We will primarily focus on (1) the pathogenesis of heart failure, (2) the molecular mechanism of neurodegeneration in adult-onset DM1 mouse model, and (3) the molecular mechanism of developmental disorders in congenital DM1 mouse model. 

研究介紹

本實驗室的研究有兩個主題:(1) 探究造成先天性心臟疾病的致病機轉; (2) 研究造成神經發育及神經退化疾病的致病機轉。我們以一顯性罕見遺傳疾病:「肌強直症」的小鼠模式,作為主要研究的工具。肌強直症為一顯性遺傳疾病,患者具有肌肉僵直、心血管系統及神經系統方面之疾病。造成疾病的主要原因是由於,數百或上千之CTG repeat 位在DMPK 基因非轉譯區,經轉錄成RNA之後形成穩定之二級結構,此RNA累積在細胞核內影響細胞之生理功能。

(1)“先天性心臟發育不全”,若是嚴重者會導致胚胎無法發育完全。然而在心臟發育過程中,不同區域的發育遲緩,常會造成心臟“隱性的”機能衰退,在特定的誘發情形下,仍會有致命的危險。利用基因轉殖動物模式,我們期望能探討,當心臟不同區域的發育遲緩時,對心臟的功能所造成的影響。

(2)「肌強直症」的患者,若神經系統發育過程受阻所造成之症狀包括,心智發展遲緩、過動及缺乏注意力集中、嗜睡、學習記憶障礙及精神方面等疾病。罹患肌強直症的病人其認知功能異常與行為偏差的比例很高,然而,目前對於造成神經系統方面的疾病之原因仍不清楚。我們希望透過研究其中的致病機轉,進而瞭解如何找到減緩疾病症狀的治療方法。

我們所建立的心臟專一(heart-specific) 及中樞神經系統專一(brain-specific) 之小鼠模式,提供了極佳的研究工具:(1)「肌強直症」雖是罕見疾病,其導致心臟衰竭的致病機轉,卻與心肌梗塞所造成的心臟衰竭,具有類似的分子機制。(2) 同樣的,將960 CTG repeats 表現在出生後成鼠之神經細胞,小鼠具有神經退化疾病; 若表現在發育中之神經細胞,小鼠則具有神經發育的問題。透過研究「肌強直症」在神經系統的致病機轉,可以進而瞭解廣泛的神經發育及神經退化形成的原因。

以「肌強直症」為例,遺傳性的罕見疾病,其成因在基因層級,有其特異性,然而病人所表現出的臨床症狀卻與許多疾病是類似的,例如,過動症,心智發展遲緩,學習障礙,心血管疾病等等。以研究導致「肌強直型肌肉萎縮症」的病人,在神經系統與心血管系統所造成的症狀,其實也是幫助我們瞭解造成其他類似臨床症狀之致病機轉的一個很好的方式。

 

Dr. Wang, Guey-Shin
王桂馨 博士

Associate Research Fellow
副研究員


Ph.D. National Yang-Ming University
Specialty:
  • Cardiovascular disease
  • Neurodegeneration
  • Neurodevelopmental disorder

HIGHLIGHT 重要成果

CELF1 promotes vascular endothelial growth factor degradation resulting in impaired microvasculature in heart failure
FASEB journal, Apr 03, 2021
Ubiquitination of MBNL1 Is Required for Its Cytoplasmic Localization and Function in Promoting Neurite Outgrowth
Cell Reports, Feb 27, 2018
CELF1 Mediates Connexin 43 mRNA Degradation in Dilated Cardiomyopathy
Circulation Research, Sep 05, 2017

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