楊豐名副教授

本實驗室領域是內分泌生理學並致力於研究先天免疫失衡在肺部疾病中的調控機轉，並開發新的治療標的。目前研究計畫主要探討先天免疫系中的嗜中性細胞胞外誘捕網與巨噬細胞焦亡的調控機制，以及其在調控過敏性發炎氣喘反應與敗血症合併急性肺損傷中的角色和機制。先天免疫系統是宿主防禦的第一道防線，能夠預防感染並清除微生物。先天免疫細胞，例如巨噬細胞，透過模式識別受體（pattern-recognition receptors, PRRs）偵測保守的微生物分子，這些分子被稱為病原相關分子模式（PAMPs）或由受損細胞釋放的危險相關分子模式（DAMPs），進而誘導促發炎性細胞激素、趨化因子、干擾素的產生。儘管促發炎性細胞激素有助於促進發炎細胞的聚集與活化抗微生物系統，但若促與抑制性細胞激素之間失衡，可能導致慢性發炎與感染性疾病的發病。因此，先天免疫反應必須受到嚴格調控，以避免失控的發炎反應。

我們特別聚焦於研究兩個重要調控因子：Protein Phosphatase 4 （PP4）與 somatic Nuclear Autoantigenic Sperm Protein（sNASP）。我們採用多種研究方法，包括分子與細胞層級的實驗，以及小鼠基因模型來探討相關問題。目前的研究重點包括：1）活化巨噬細胞中 TLR 訊號傳導的分子機制；2）內質網壓力（ER stress）與細胞自噬（Autophagy）在嗜中性細胞胞外誘捕網與巨噬細胞焦亡活化的機制；3）PP4 基因表現的調控。

另外，過敏性氣喘所造成的肺部上皮細胞間質轉化的發生，經常與細胞屏障破損和慢性第二型發炎反應有密切關係。而肺部細菌感染與急性肺損傷所誘發的細胞激素風暴，亦是目前臨床急重症急需解決課題之一。因此，我們專注於探索先天性免疫受體 TLR4 誘發之 sNASP/TRAF6 訊息通路在肺部疾病的調控機轉，並進一步開發潛在的治療標的。因此，我們在

1.急性肺損傷的研究中發現磷酸化的 sNASP 蛋白是先天性免疫受體 TLR4 活化下游 TRAF6 訊息通路所生成細胞激素風暴中的關鍵調控因子。而蛋白質去磷酸酶 PP4 能專一性造成 sNASP 蛋白去磷酸化，進而抑制 TRAF6 訊息通路與細胞激素風暴生成，並能減緩敗血症所引發的小鼠死亡率及肺部損傷。另外，本團隊設計出 PEP-sNASP 胜肽能專一性抑制 TRAF6 活化與細胞激素風暴生成，並能降低敗血症所引發的小鼠死亡率及肺部損傷。

2.過敏性氣喘的研究中發現在塵蟎刺激下會大量增加 TLR2/4 受體表現，進而活化 sNASP/TRAF6 訊息軸來造成肺上皮細胞產生大量的粘蛋白 (mucin) 產生，加重過敏性氣喘的產生。空氣污染會明顯地造成支氣管上皮細胞中PP4的表現量的下降，此現象也在患有嚴重過敏性氣喘病人中的肺上皮細胞中發現。PP4的缺失會造成 Src 蛋白磷酸化上升，進而造成緊密蛋白缺失以及上皮細胞屏障的破壞。同時也會促進 EGFR 受體磷酸化來增加警報蛋白的合成與釋放，進而惡化空污所造成的過敏性氣喘。

最後，本實驗室也將探討內分泌與免疫系統在發炎性疾病與氣喘中的交互作用機轉，內分泌激素，包括糖皮質激素與性激素，對免疫反應與發炎過程具有顯著影響。激素失調會加劇發炎性疾病，並可能在氣喘的致病機制中扮演關鍵角色。透過分子機制（例如對 sNASP或PP4 相關途徑的調控）調控內分泌與免疫系統，有望提供治療的新靶點。

實驗室技術：

1.基因改造鼠: Cre-loxP system, CRISPR/Cas9 knock-in mice

2.動物模式: CLP- and LPS-induced Sepsis Models, OVA- and HDM-induced Asthma Models 。

3.細胞株模式: 呼吸道上皮細胞株與免疫細胞株培養, Air liquid interface cell culture。

4.病毒載體技術: adenovirus, lentivirus。

5.組織免疫學: immunohistochemistry, immunofluorescence

6.生化與影像技術: Western blotting, immunoprecipitation, immunofluorescent imaging, flow cytometry, confocal imaging analysis.

7.分子生物技術: plasmid construction, RNA and DNA extraction, RT-PCR, gene knockdown by siRNA and lentiviral-medited shRNA, site-directed mutagenesis, transfection and transformation.

8.特殊設備: 海馬生物能量代謝測定儀, Transepithelial Electrical Resistance (TEER), Electroporator, fluorescent microscope equipped with digital camera, Refrigerated Homogenizer and microcentrifuge.

9.生物資訊: Bulk RNA-seq, Single-cell RNA-seq (scRNA-seq) and Whole-genome sequence (WGS

PUBLICATIONS

• Firdian Makrufardi, Syue-Wei Peng, Kian Fan Chung, Marc Chadeau-Hyam, Kang-Yun Lee, Ta-Chih Hsiao, Kin-Fai Ho, Desy Rusmawatiningtyas, Indah Kartika Murni, Eggi Arguni, Yuan-Hung Wang, Shu-Chuan Ho, Feng-Ming Yang, Kai-Jen Chuang, Sheng-Chieh Lin, Hsiao-Chi Chuang (2025) Extreme temperatures modulate gene expression in the airway epithelium of the lungs in mice and asthma patients. Front Med (Lausanne). 2025 Apr 17:12:1531154. doi: 10.3389/fmed.2025.1531154. (SCI)

• Yu-Chih Wu, Bing-Hua Su, Wun-Hao Cheng, Cheng-Tai Zou, Edward T H Yeh, Feng-Ming Yang (2025) CYLD links the TRAF6/sNASP axis to TLR4 signaling in sepsis-induced acute lung injury. CMLS. 2025 Mar 20;82(1):124 (SCI)

• Huan Minh Tran, Feng-Jen Tsai, Yuan-Hung Wang, Kang-Yun Lee, Jer-Hwa Chang, Chi-Li Chung, Chien-Hua Tseng, Chien-Ling Su, Yuan-Chien Lin, Tzu-Tao Chen, Kuan-Yuan Chen, Shu-Chuan Ho, Feng-Ming Yang, Sheng-Ming Wu, Kian Fan Chung, Kin-Fai Ho, Kai-Jen Chuang, Hsiao-Chi Chuang (2025) Joint effects of temperature and humidity with PM2.5 on COPD. CMLS. BMC Public Health. 2025 Feb 3;25(1):424. doi: 10.1186/s12889-025-21564-3. (SCI)

• Huan Minh Tran, Feng-Jen Tsai, Kang-Yun Lee, Yuan-Hung Wang, Feng-Ming Yang, Shu-Chuan Ho, Hanh Thi My Bui, Linh Nhat Nguyen Hoang, Linh Thi My Bui, Kin-Fai Ho, Kian Fan Chung, Kai-Jen Chuang, Hsiao-Chi Chuang (2025) Extreme temperature increases the risk of COPD morbimortality: A systematic review and meta-analysis. Sci Total Environ. 2025 Jan 1:958:178087. (SCI)

• Hao-Hua Jiang, Tzu-Hsuan Wu, Li-Jen Lee, Jui-Chen Lee, Bon-Chu Chung, Feng-Ming Yang, Meng-Chun Hu (2024) Dendritic Morphology of Developing Hippocampal Neurons in Cyp11a1 Null Mice. Dev Neurosci. 2024 Jul 17:1-15. doi: 10.1159/000540106 (SCI)

• Shao-An Wang, Yu-Chih Wu, Feng-Ming Yang, Feng-Lin Hsu, Kuan Zhang, Jan-Jong Hung (2023) NCI677397 targeting USP24-mediated induction of lipid peroxidation induces ferroptosis in drug-resistant cancer cells. Mol Oncol. 2023 Dec 22; doi: 10.1002/1878-0261.13574 (SCI)

• Yi-Hsuan Kuo, Tsai-Chun Lai, Chia-Hsin Chang, Han-Ching Hsieh, Feng-Ming Yang, Meng-Chun Hu (2023) 5,6-Dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) induces apoptosis in breast cancer cells through inhibiting of Mcl-1 expression. Sci Rep. 2023 Aug 3;13(1):12621; doi: 10.1038/s41598-023-39340-x (SCI)

• Feng-Ming Yang, Meng-Chun Hu, Chih-Ming Weng, Hsiao-Chi Chuang, Yu-Ting Lan, Bing-Hua Su, Kyung-Sun Heo, Han-Pin Kuo (2023) Loss of PP4 contributes to diesel exhaust particles-induced epithelial barrier integrity disruption and alarmins release. Allergy. 2023 Jun;78(6):1670-1673 (SCI)

• Ming-Zhen Chen, Shao-An Wang, Shih-Chang Hsu, Kleiton Augusto Santos Silva and Feng-Ming Yang (2022) Home Dust Mites Promote MUC5AC Hyper-Expression by Modulating the sNASP/TRAF6 Axis in the Airway Epithelium. Int J Mol Sci. 2022 Aug 20;23(16):9405 (SCI)

• Yu-Chih Wu, Sung-Po Hsu, Meng-Chun Hu, Yu-Ting Lan, Edward T. H. Yeh and Feng-Ming Yang (2022) PEP-sNASP Peptide Alleviates LPS-Induced Acute Lung Injury Through the TLR4/TRAF6 Axis. Front Med (Lausanne). 2022 Mar 21;9:832713 (SCI)

• Feng-Ming Yang, Hui-Ming Chang and Edward T.H. Yeh (2021) Regulation of TLR4 signaling through the TRAF6/sNASP axis by reversible phosphorylation mediated by CK2 and PP4. Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2107044118 (SCI)

• Feng-Ming Yang, Yong Zuo, Wei Zhou, Chuan Xia, Bumsuk Hahm, Mark Sullivan, Jinke Cheng, Hui-Ming Chang and Edward T.H. Yeh (2018) sNASP inhibit TLR Signaling to Regulates Immune Response in Sepsis. J Clin Invest. 2018 Jun 1;128(6):2459-2472 (SCI)

• Tasneem Bawa-Khalfe, Feng-Ming Yang, Joan Ritho, Hui-Kuan Lin, Jinke Cheng, and Edward T.H. Yeh (2016) SENP1 regulates PTEN stability to dictate prostate cancer development. Oncotarget. 2017 Mar 14;8(11):17651-17664 (SCI)

• Feng-Ming Yang, Shan- Jung Feng and Meng-Chun Hu (2015) A calreticulin-dependent nuclear export signal is involved in the regulation of liver receptor homologue-1 protein folding. Biochem J. 2015 Oct 15;471(2):199-209 (SCI)

• Yuan-Ching Chang, Chien-Liang Liu, Ming-Jen Chen, Yung-Wei Hsu, Shan-Na Chen, Chi-Hsin Lin, Chin-Man Chen, Feng-Ming Yang, and Meng-Chun Hu, (2014) Local Anesthetics Induce Apoptosis in Human Breast Tumor Cells Anesth Analg. 2014 Jan;118(1):116-124 (SCI)

• Feng-Ming Yang and Meng-Chun Hu (2011) Identification of two functional nuclear localization signals mediating nuclear import of liver receptor homolog-1. Cell Mol Life Sci. 2011 Apr;68(7):1241-1253 (SCI)

•I-Fen Lu, Ann-Che Hasio, Meng-Chun Hu, Feng-Ming Yang, Hui-Min Su (2010) Docosahexaenoic acid induces proteasome-dependent degradation of estrogen receptor α and inhibits the downstream signaling target in MCF-7 breast cancer cells. J Nutr Biochem. 2010 Jun;21(6):512-7 (SCI)

• Feng-Ming Yang, Chien-Ting Pan, Huei-Man Tsai, Tai-Wei Chiu, Mei-Ling Wu and Meng-Chun Hu (2009) Liver receptor homolog-1 localization in the nuclear body is regulated by sumoylation and cAMP signaling in rat granulosa cells. FEBS J. 2009 Jan;276(2):425-36 (SCI)

• Hsiang-Tsan Hsieh, Chih-Hung Wang, Mei-Ling Wu, Feng-Ming Yang, Yu-Chen Tai and Meng-Chun Hu (2009) PIASy inhibits LRH-1-dependent CYP11A1 expression by competing for SRC-1 binding. Biochem J. 2009 Apr 1;419(1):201-9 (SCI)

• Jin-Ching Lee, Tzong-Yuan Wu, Chien-Fu Huang, Feng-Mine Yang, Shin-Ru Shih, John T.A. Hsu (2005) High-efficiency protein expression mediated by enterovirus 71 internal ribosome entry site. Biotechnol Bioeng. 2005 Jun 5;90(5):656-62 (SCI)

Research Interests

Our laboratory focuses on investigating how innate immune imbalance contributes to lung diseases and aims to develop potential therapeutic targets. Key research areas include the regulation of neutrophil extracellular traps (NETs) and macrophage pyroptosis, the roles of PP4 and sNASP proteins in acute lung injury and allergic asthma, and their involvement in ER stress, autophagy, and cytokine storm formation. We found that PP4 suppresses the sNASP/TRAF6 signaling axis, reducing lung inflammation and damage, and developed a therapeutic peptide, PEP-sNASP, with promising effects. Air pollution significantly lowers PP4 expression in bronchial epithelial cells, weakening the epithelial barrier and worsening asthma symptoms. We also explore how endocrine hormones—such as glucocorticoids and sex hormones—interact with the immune system in inflammatory diseases and asthma. Targeting PP4 and sNASP-related pathways may offer new strategies for treatment.

Thus, the research directions of my lab include

Protein Kinases and Phosphatases in Innate Immune Cell Signaling
Inflammation-induced Lung Diseases (ALI and Asthma)
Therapeutic agents targeting the regulation of innate immunity
Endocrine Dysregulation

Laboratory Techniques

Genetically modified mice: Cre-loxP system, CRISPR/Cas9 knock-in mice
Animal models: CLP- and LPS-induced Sepsis Models, OVA- and HDM-induced Asthma Models 。
Cell culture models: airway epithelial cells and immune cells, Air liquid interface cell culture。
Virus-delivered technologies: adenovirus, lentivirus。
Tissue histopathology: immunohistochemistry, immunofluorescence
Biochemical and imaging technologies: Western blotting, immunoprecipitation, immunofluorescent imaging, flow cytometry, confocal imaging analysis.
Molecular biology: plasmid construction, RNA and DNA extraction, RT-PCR, gene knockdown by siRNA and lentiviral-mediated shRNA, site-directed mutagenesis, transfection and transformation.
Special equipment: Seahorse, Transepithelial Electrical Resistance (TEER), Electroporator, fluorescent microscope equipped with digital camera, Refrigerated Homogenizer and microcentrifuge.
Bio information: Bulk RNA-seq, Single-cell RNA-seq (scRNA-seq) and Whole-genome sequence (WGS)

Publication list