Dr. Wang, Guey-Shin ’s Lab王桂馨 博士 實驗室

RESEARCH

Our research focuses on two main projects in understanding (1) the regulatory mechanism involved in the transition from compensation to decompensation and heart failure, and, (2) the neural pathogenesis of congenital myotonic dystrophy. 

Re-induction of fetal gene program is associated with pathological cardiacremodeling. How the fetal gene program is activated and whether reinduction of fetal gene program in adult heart contributes to adverse cardiac phenotypes remains largely unclear. Whether induction of fetal gene program is differentially regulated in the transition from adaptive or compensatory stage to decompensation and heart failure also remains elusive. CELF1 (CUGBP Elav-like family member 1) is an RNA-binding protein that regulates alternative splicing and mRNA degradation. CELF1 is highly expressed in embryonic heart and down-regulated in adult heart. We have recently shown that elevated CELF1 expression in dilated cardiomyopathy (DCM), the most common cause of heart failure, causes degradation of connexin 43 and vascular endothelial growth factor (Vegf) mRNAs leading to conduction defect and vascular rarefaction. While the results suggest a pathogenic role for CELF1 during heart failure and CELF1 might be a potential therapeutic target in heart failure, it is still unclear the functional role of CELF1 during heart development. It remains elusive whether CELF1-regulated fetal gene programs during embryonic development and pathological condition are similar or distinct. Therefore, our goals are to understand the functional role of CELF1 during heart development and determine whether CELF1 could be a potential therapeutic target in heart failure. 

Cognitive deficits are found in a high percentage of individuals with myotonic dystrophy type 1 (DM1). The cognitive impairments include mental retardation, anxiety, autism spectrum disorder (ASD), depression and attention deficit hyperactivity disorders (ADHD). The genetic basis of DM1 is caused by an expansion of CTG repeats in the 3’ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. DMPK mRNA containing expanded CUG repeats accumulates in nuclear foci and affect nuclear and cytoplasmic activities of RNA binding protein such as muscleblind like (MBNL). We previously generated a mouse model for postnatal expression of expanded CUG RNA in the brain that recapitulates several features of adult-onset DM1 including learning disability, neurodegeneration and misregulated RNA processing. How expanded CUG RNA affects early stage of neurodevelopment remains largely unknown. To understand this, we have generated a mouse model of congenital DM1 and investigated how expanded CUG RNA affects RNA processing during neurogenesis.  

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
  • TEL(office):2652-3051
  • TEL(lab):2789-9051 (Room No: 206)
  • FAX:2782-3047

Specialty:
  • Cardiovascular disease
  • Neurodegeneration
  • Neurodevelopmental disorder

HIGHLIGHT 重要成果

Calpain-2 Mediates MBNL2 Degradation and a Developmental RNA Processing Program in Neurodegeneration
Journal of Neuroscience, May 23, 2022
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

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