[Tyra Talk] 2025-03-15 化學蛋白質體學應用: 針對自體免疫疾病的新藥開發
SLC15A4 是一種溶酶體的轉運蛋白，與自身炎症及自身免疫相關。SLC15A4 在多種免疫細胞亞群中對於 7-9 型 Toll 樣受體（TLRs）及含核苷酸結合寡聚化結構域的蛋白（NOD）信號傳導至關重要。研究指出，SLC15A4 在小鼠系統性紅斑狼瘡的發展中起關鍵作用，與人類自身免疫疾病相關。儘管具有治療潛力，但針對 SLC15A4 功能的高品質化學探針仍十分有限。本研究利用整合化學蛋白質組學方法，開發出一系列化學工具，包括首創功能性抑制劑。我們證明這些抑制劑可抑制 SLC15A4 介導的溶酶體 TLR 和 NOD 功能，並在多種人類及小鼠免疫細胞中發揮作用。此外，我們提供證據顯示其可在體內及臨床環境中抑制炎症，並解析其作用機制。我們的研究確立了 SLC15A4 作為治療自身免疫及自身炎症疾病的潛在藥物靶點。
|| 講者（Speaker）:
邱子源（Tzu-Yuan Chiu）
Today’s speaker is Tzu-Yuan Chiu. Tzu-Yuan is a fifth-year grad student from Scripps Research. His research focuses on using small molecules to discover new biology for autoimmune diseases.
Tzu-Yuan is from Taichung, and he studied material science and engineering during his undergraduate studies at National Taiwan University. He then switched to the field of molecular biology during his master’s degree. Inspired by the training and the sense of achievement when doing biology research in NTU and Academia Sinica, he decided to apply to grad school in the States to pursue his PhD. With a strong background in molecular, cellular biology and immunology, Tzu-Yuan decided to join Chris Parker’s lab, who is an expert in discovering new biological targets with fragment-based small molecules and proteomics. He has been dedicated to understanding the function and the mechanisms of their newly identified SLC15A4 inhibitor, which suppresses autoinflammatory cytokines production in vitro and in vivo. Today, he will talk about his story on how he discovered this compound and how he discovered the underlying biology.
|| 摘要（Abstract）:
SLC15A4 is an endolysosome-resident transporter linked with autoinflammation and autoimmunity. Specifically, SLC15A4 is critical for Toll-like receptors (TLRs) 7–9 as well as nucleotide-binding oligomerization domain-containing protein (NOD) signaling in several immune cell subsets. Notably, SLC15A4 is essential for the development of systemic lupus erythematosus in murine models and is associated with autoimmune conditions in humans. Despite its therapeutic potential, the availability of quality chemical probes targeting SLC15A4 functions is limited. In this study, we used an integrated chemical proteomics approach to develop a suite of chemical tools, including first-in-class functional inhibitors, for SLC15A4. We demonstrate that these inhibitors suppress SLC15A4-mediated endolysosomal TLR and NOD functions in a variety of human and mouse immune cells; we provide evidence of their ability to suppress inflammation in vivo and in clinical settings; and we provide insights into their mechanism of action. Our findings establish SLC15A4 as a druggable target for the treatment of autoimmune and autoinflammatory conditions.
|| 研究領域（Field）:
自然科學、數學及統計領域；醫藥衛生及社會福利領域
|| 研究子領域（Sub-field）:
化學生物
|| 主持人（Chair）:
|| 活動時間（Event Time）:
03/15/2025 07:00 PM PDT Pacific Time
03/15/2025 08:00 PM MDT Mountain Time
03/15/2025 09:00 PM CDT Central Time
03/15/2025 10:00 PM EDT Eastern Time
03/16/2025 02:00 AM GMT England
03/16/2025 03:00 AM CET Berlin
03/16/2025 10:00 AM Taiwan
|| 圖像設計（Design）:
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