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邱清旗 副教授

邱清旗 (Ching-Chi Chiu)
邱清旗

學歷

長庚大學生物醫學研究所博士

任課科目

臨床生理學、分子生物學、生技學研究實驗、醫用生物技術學

研究專長

神經科學、神經退化疾病、細胞分子生物學、誘導性多功能幹細胞、突變帕金森病基因嵌入小鼠、生物化學 、醫學生物技術

辦公室分機

3708

實驗室分機

5097

個人網頁

神經退化疾病研究室

E-mail

ccchei@mail.cgu.edu.tw

ccchei178@gmail.com

研究方向及研究室特色(Lab & Research Interest)

台灣帕金森病患者高達十萬人，且帕金森病影響到的不只是個人，更會帶來整個家庭經濟、身心的重大壓力及負擔，本人以帕金森病為研究主軸，探討神經退化病理機轉，持續發展早期診斷與臨床治療而努力，也期許自己能真正幫助到全台灣十萬個瀕臨疾病壓力的家庭。由於基礎及臨床人力、物力資源的適切整合，本人得以從基礎神經科學和臨床病徵同時出發，相互驗證。從臨床檢體、臨床資料收集到實驗室分子生物實驗、動物模式的建立等，研究病理機轉、開發小分子藥物到臨床診斷的應用，連結基礎研究與臨床診斷，兼具有經濟價值和正面的社會影響。

實驗室目前積極發展帕金森病(Parkinson’s disease)相關研究:

1.    帕金森病生物標記的開發

  我們實驗室利用蛋白質體與轉錄體學發現帕金森病患者血清檢體有大量RAB35蛋白質與microRNA-204-5p的表現。我們研究發現藉由檢測病患血清Rab35與α-synuclein表現量，不僅提供臨床早期診斷帕金森病，更能精確區分在臨床症狀難以分別的帕金森病、多重系統退化症與進行性上核麻痺症。在帕金森病病患血清檢體和MPTP誘導帕金森病小鼠的中腦組織都具有大量表現的miR-204-5p，進而活化DYRK1A基因表現，進而引起磷酸化α-synuclein和磷酸化Tau的增加，造成內質網壓力和細胞自吞噬損壞(autophagy impairment)，導致多巴胺神經細胞死亡。發展生物標記能及早治療帕金森病，提供病患未來更好的生活品質。

2.    突變帕金森病基因嵌入小鼠之應用

 實驗室建立世界首創早發性(early-onset)神經退化之帕金森病小鼠，並發現突變PLA2G6基因引起神經退化之機轉。突變PLA2G6基因嵌入小鼠能提供作為開發神經保護藥物的活體藥物篩選平台。實驗室同時也建立其他突變帕金森病基因嵌入小鼠，進行研究帕金森病分子機轉研究。

3.    帕金森病患者誘導性多能幹細胞(iPSCs)

  我們實驗室已從具有突變(D331Y/M358IfsX) PLA2G6帕金森病患者血液檢體，建立誘導式多功能幹細胞，並能分化為多巴胺神經細胞，除了探討突變PLA2G6造成神經退化機轉外，積極發展帕金森病的細胞治療。實驗室建立帶有其他突變帕金森病基因的誘導性多能幹細胞，進行神經退化機轉研究。

4.    神經保護藥物與小分子開發

  實驗室發現研究發現，小分子化合物Alda-1能專一的與ALDH2蛋白結合並增加其活性，利用Alda-1活化多巴胺神經細胞內的ALDH2，不僅能減緩神經毒素誘導產生的自由基產生，也能維持粒線體膜電位和粒線體複合物活性，產生神經保護作用。在帕金森病小鼠模式也進一步證實，ALDH2的活化能減緩小鼠黑質區內自由基的產生，也抑制粒線體調控細胞凋亡路徑的活化，產生神經保護作用。此研究結果提供ALDH2活化在帕金森病與其他神經退化疾病的治療應用和藥物開發。實驗室也積極開發其他神經保護藥物與小分子，期望未來能提供臨床病患治療。

5.    未來研究方向

  除了積極研究帕金森病外，實驗室也積極發展阿茲海默症(Alzheimer's disease)相關研究，利用臨床檢體、阿茲海默病患誘導性多能幹細胞與阿茲海默症相關基因嵌入小鼠進行神經退化之機轉與治療開發。

論文與著作(Publication)

I. 論文

  1. Wang HL, Yeh TH, Huang YZ, Weng YH, Chen RS, Wei KC, Lu CS, Liu YC, Shen YM, Chen CL, Chen YJ, Hsu CC, Chiu CH, Lin YW, Chiu CC* (*Corresponding author). Functional variant rs17525453 within RAB35 gene promoter is possibly associated with increased risk of Parkinson's disease in Taiwanese population. Neurobiology of Aging. 2021 (Accepted) IF= 4.347, Ranking= 10/51; 19.60% (Geriatrics & Gerontology).
  2. Chiu CC, Weng YH, Huang YZ, Chen RS, Liu YC, Yeh TH, Lu CS, Lin YW, Chen YJ, Hsu CC, Chiu CH, Wang YT, Chen WS, Liu SY, Wang HL. (D620N) VPS35 causes the impairment of Wnt/β-catenin signaling cascade and mitochondrial dysfunction in a PARK17 knockin mouse model. Cell Death Dis. 2020 Nov 30;11(11):1018. doi: 10.1038/s41419-020-03228-9. IF= 6.304, Ranking= 40/195; 20.51% (Cell Biology).
  3. Liu YC, Wang HL, Huang YZ, Weng YH, Chen RS, Tsai WC, Yeh TH, Lu CS, Chen YL, Lin YW, Chen YJ, Hsu CC, Chiu CH, Chiu CC* (*Corresponding author). Alda-1, an activator of ALDH2, ameliorates Achilles tendinopathy in cellular and mouse models. Biochem Pharmacol. 2020 Mar 16:113919. doi:10.1016/j.bcp.2020.113919. IF= 4.960, Ranking= 26/270; 9.815% (Pharmacology & Pharmacy).
  4. Wang HL, Lu CS, Yeh TH, Shen YM, Weng YH, Huang YZ, Chen RS, Liu YC, Cheng YC, Chang HC, Chen YL, Chen YJ, Lin YW, Hsu CC, Chiu CC* (*Corresponding author). Combined assessment of serum alpha-synuclein and Rab35 is a better biomarker for Parkinson's disease. J Clin Neurol. 2019 Oct;15(4):488-495. IF= 2.439, Ranking= 112/204; 54.90% (Clinical Neurology).
  5. Chiu CC, Yeh TH, Chen RS, Chen HC, Huang YZ, Weng YH, Cheng YC, Liu YC, Cheng AJ, Lu YC, Chen YJ, Lin YW, Hsu CC, Chen YL, Lu CS, Wang HL. Upregulated expression of microRNA-204-5p leads to the death of dopaminergic cells by targeting DYRK1A-mediated apoptotic signaling cascade. Front Cell Neurosci. 2019 Sep 13; 13:399. IF=3.921, Ranking= 91/271; 33.40% (Neuroscience).
  6. Chiu CC, Wang HL, Weng YH, Chen RS, Chen CM, Yeh TH, Lu CS, Chen YJ, Liu YC, Huang YZ and Chang KH. Generation of induced pluripotent stem cells from a young-onset Parkinson's disease patient carrying the compound heterozygous PLA2G6 p.D331Y/p.M358IfsX mutations. Stem Cell Res. 2019 Oct; 40:101552. IF= 4.489, Ranking= 27/156; 16.987% (Biotechnology & Applied microbiology).
  7. Chiu CC, Lu CS, Weng YH, Chen YL, Huang YZ, Chen RS, Cheng YC, Huang YC, Liu YC, Lai SC, Lin KJ, Lin YW, Chen YJ, Chen CL, Yeh TH, Wang HL. PARK14 (D331Y) PLA2G6 causes early-onset degeneration of substantia nigra dopaminergic neurons by inducing mitochondrial dysfunction, ER stress, mitophagy impairment and transcriptional dysregulation in a knockin mouse model. Mol Neurobiol. 2019 Jun;56(6):3835-3853. IF= 4.500, Ranking= 65/272; 23.897% (Neuroscience); 59/366; 16.12% (Neuroscience & Behavior).
  8. Yeh TH, Liu HF, Li YW, Lu CS, Shih HY, Chiu CC, Lin SJ, Huang YC, Cheng YC. C9orf72 is essential for neurodevelopment and motility mediated by Cyclin G1. Exp Neurol. 2018 Mar 6;304: 114-124. IF= 4.691, Ranking= 59/271; 21.587% (Neuroscience); 36/365 (Neuroscience & Behavior).
  9. Chiu CC, Yeh TH, Lu CS, Huang YC, Cheng YC, Huang YZ, Weng YH, Liu YC, Lai SC, Chen YL, Chen YJ, Chen CL, Chen HY, Lin YW, Wang HL. PARK14 PLA2G6 mutants are defective in preventing rotenone-induced mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway. Oncotarget. 2017 Sep 15;8(45):79046-79060. Ranking=62/321 (Oncology).
  10. Huang YC, Lin SJ, Shih HY, Chou CH, Chu HH, Chiu CC, Yuh CH, Yeh TH, Cheng YC. Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation. Oncotarget. 2017 Jun 27;8(38):63110-63120. Ranking=62/321 (Oncology).
  11. Chiu CC, Yeh TH, Lai SC, Huang YC, Chen YJ, Chen CL, Wang HL, Lu CS. Increased Rab35 expression is a potential biomarker and implicated in the pathogenesis of Parkinson's disease. Oncotarget. 2016 Aug 23;7(34):54215-54227. Ranking=62/321 (Oncology).
  12. Cheng YC, Huang YC, Yeh TH, Shih HY, Lin CY, Lin SJ, Chiu CC, Huang CW, Jiang YJ. Deltex1 is inhibited by the Notch-Hairy/E(Spl) signaling pathway and induces neuronal and glial differentiation. Neural Dev. 2015 Dec 30;10:28. IF= 2.630; 40.244% Ranking= 17/41 (Developmental Biology); 167/271, 61.439% (Neuroscience).
  13. Chou AH, Chen YL, Chiu CC, Yuan SJ, Weng YH, Yeh TH, Lin YL, Fang JM, Wang HL. T1-11 and JMF1907 ameliorate polyglutamine-expanded ataxin-3-induced neurodegeneration, transcriptional dysregulation and ataxic symptom in the SCA3 transgenic mouse. Neuropharmacology. 2015 Aug 6;99:308-317. IF= 4.431, 43/271; 15.87% (Pharmacology & Pharmacy). 68/272; 25% (Neuroscience)
  14. Chiu CC, Yeh TH, Lai SC, Wu-Chou YH, Chen CH, Mochly-Rosen D, Huang YC, Chen YJ, Chen CL, Chang YM, Wang HL, Lu CS. Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Exp Neurol. 2015 Jan; 263:244-53. IF= 4.691, Ranking=60/267, 21.59% (Neuroscience); 36/365 (Neuroscience & Behavior).
  15. Huang YC, Shih HY, Lin SJ, Chiu CC, Ma TL, Yeh TH, Cheng YC. The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation. Dev Neurobiol. 2015 May;75(5):452-62. IF= 3.935, Ranking= 8/41 (Developmental Biology); 89/271, 18.293% (Neuroscience).
  16. Chiu CC, Lee LY, Li YC, Chen YJ, Lu YC, Li YL, Wang HM, Chang JT, Cheng AJ. Grp78 as a therapeutic target for refractory head-neck cancer with CD24(-)CD44(+) stemness phenotype. Cancer Gene Ther. 2013 Nov;20(11):606-15. IF= 4.534, Ranking= 25/156; 15.705% (Biotechnology & Applied microbiology).
  17. Chen YJ, Lee LY, Chao YK, Chang JT, Lu YC, Li HF, Chiu CC, Li YC, Li YL, Chiou JF, Cheng AJ. DSG3 facilitates cancer cell growth and invasion through the DSG3-plakoglobin-TCF/LEF-Myc/cyclin D1/MMP signaling pathway. PLoS One. 2013 May 30;8(5): e64088. IF= 2.740, Ranking= 27/71; 37.324% (Multidisciplinary Sciences).
  18. Chiu CC, Lin CY, Lee LY, Chen YJ, Lu YC, Wang HM, Liao CT, Chang JT, Cheng AJ. Molecular chaperones as a common set of proteins that regulate the invasion phenotype of head and neck cancer. Clin Cancer Res. 2011 Jul 15; 17(14):4629-41. IF= 10.107, Ranking= 17/244; 6.762% (Oncology).
  19. Lin TY, Chang JT, Wang HM, Chan SH, Chiu CC, Lin CY, Fan KH, Liao CT, Chen IH, Liu TZ, Li HF, Cheng AJ. Proteomics of the radioresistant phenotype in head-and-neck cancer: Gp96 as a novel prediction marker and sensitizing target for radiotherapy. Int J Radiat Oncol Biol Phys. 2010 Sep 1;78(1):246-56. IF= 5.859, Ranking= 10/133; 7.143 (Radiology, nuclear medicine and imaging).
  20. Chang JT, Kuo TF, Chen YJ, Chiu CC, Lu YC, Li HF, Shen CR, Cheng AJ. Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers. Cancer Gene Ther. 2010 Dec;17(12):827-36. IF= 4.534, Ranking= 25/156; 15.705% (Biotechnology & Applied microbiology).
  21. Lin CY, Chen WH, Liao CT, Chen IH, Chiu CC, Wang HM, Yen TC, Lee LY, Chang JT, Cheng AJ. Positive association of glucose-regulated protein 78 during oral cancer progression and the prognostic value in oral precancerous lesions. Head Neck. 2010 Aug; 32(8):1028-39. IF= 2.538, Ranking= 9/42; 20.238% (Otorhinolaryngology).
  22. Kang CJ, Chen YJ, Liao CT, Wang HM, Chang JT, Lin CY, Lee LY, Wang TH, Yen TC, Shen CR, Chen IH, Chiu CC, Cheng AJ. Transcriptome profiling and network pathway analysis of genes associated with invasive phenotype in oral cancer. Cancer Lett. 2009 Nov 1;284 (2):131-40. Epub 2009 May 19. IF= 7.360, Ranking= 30/244, 12.09 % (Oncology).
  23. Chiu CC, Lin CY, Lee LY, Chen YJ, Kuo TF, Chang JT, Liao CT, Wang HM, Yen TC, Shen CR, Liao SK, Cheng AJ. Glucose-regulated protein 78 regulates multiple malignant phenotypes in head and neck cancer and may serve as a molecular target of therapeutic intervention. Mol Cancer Ther. 2008 Sep; 7(9):2788-97. IF= 5.615, Ranking= 50/244, 20.287% (Oncology).
  24. Chen YJ, Chang JT, Liao CT, Wang HM, Yen TC, Chiu CC, Lu YC, Li HF, Cheng AJ. Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer Sci. 2008 Aug;99(8):1507-14. IF= 4.966, Ranking= 65/244, 26.434% (Oncology).
  25. Chen YJ, Chang JT, Lee L, Wang HM, Liao CT, Chiu CC, Chen PJ, Cheng AJ. DSG3 is overexpressed in head neck cancer and is a potential molecular target for inhibition of oncogenesis. Oncogene. 2007 Jan 18;26(3):467-76. IF= 7.971, Ranking= 26/244, 10.451% (Oncology).

II. 獲獎情形

  1. Outstanding Research Paper Award in Dec 2020, Chang Gung Memorial Hospital, Taiwan (長庚醫院優秀論文).
  2. Ta-You Wu Memorial Award in Sep 2020, MOST (吳大猷先生紀念獎)
  3. Outstanding Research Paper Award in May 2020, Chang Gung Memorial Hospital, Taiwan (長庚醫院優秀論文).
  4. Outstanding Research Paper Award in June 2019, Chang Gung Memorial Hospital, Taiwan (長庚醫院優秀論文).
  5. 2018 Society for Neuroscience (SfN)-Merck Travel Award
  6. Outstanding Research Paper Award in May 2018, Chang Gung Memorial Hospital, Taiwan (長庚醫院優秀論文).
  7. Outstanding Research Paper Award in August 2016, Chang Gung Memorial Hospital, Taiwan (長庚醫院優秀論文).
  8. Second place prize at the 2rd Annual Contest of Master Thesis.
  9. College Student Research Creativity Award (2002 NSC)

III. 專利

A. 神經退化疾病(帕金森病)相關專利

發明專利名稱: 早發型帕金森病(D331Y) PLA2G6突變基因嵌入模式與藥物篩選平台和方法，發明人:邱清旗、王鴻利、葉篤學，中華民國專利字號: I695891，專利權期間: 2020/6/11~ 2039/1/2

B. 癌症相關專利

1.發明專利名稱:專一性抑制葡萄糖調節蛋白78 (Grp78)表現之RNA干擾(RNAi)序列、抑制藥劑及抑制方法，發明人:鄭恩加、張東杰、邱清旗，中華民國專利字號:I-371285、專利權期間: 2012年9月1日~ 2028年1月10日

2.發明專利名稱: Specific Grp78 expression- inhibition RNAi sequence, medicine thereof and method thereof _ a method for head and neck cancer，發明人:鄭恩加、張東杰、邱清旗，美國專利字號:US 7,825,100 B2，專利權期間: 2010/11/2 ~ 2028/7/17

3.發明專利名稱:Specific Grp78 expression- inhibition RNAi sequence, medicine thereof and method thereof _ specific Grp78-RNAi sequence.，發明人:鄭恩加、張東杰、邱清旗，美國專利字號:US 7,829,695 B2，專利權期間:2010/11/9/2010 ~ 2028/7/17
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