Decoding the functional pleiotropy of IL-20Rβ ligands in inflammation and tumorigenesis

解码 IL-20Rβ 配体在炎症和肿瘤发生中的功能多效性

• 批准号: 10350447
• 负责人: Robert Andrew Saxton
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-20 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10350447
• 关键词: Adrenal Cortex Hormones; Affinity; Agonist; Binding; Binding Sites; Biological Assay; Biophysics; Cell Line; Cells; Chronic; Colitis; Colon; Colon Carcinoma; Complex; Development; Directed Molecular Evolution; Disease; Engineering; Environment; Epithelial Cells; Epithelium; Esophageal Tissue; Esophagus; Family; Gastrointestinal tract structure; Gene Expression; Gene Expression Profiling; Homeostasis; IL24 gene; Immune; Immune system; Immunologic Surveillance; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Laboratories; Large Intestine Carcinoma; Ligands; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Monitor; Mucous Membrane; Mus; Nature; Organism; Organoids; Pathogenicity; Pathology; Pathway interactions; Patients; Play; Predisposition; Prevention; Production; Protein Engineering; Receptor Signaling; Regimen; Research; Risk; Risk Factors; Role; Severity of illness; Signal Transduction; Site; Skin; Specificity; Structure; Surface; Therapeutic; Tissues; Triage; Tumor Promotion; Up-Regulation; Variant; Yeasts; alternative treatment; antagonist; anti-tumor immune response; autoinflammatory diseases; cancer type; chronic inflammatory disease; colitis associated cancer; combinatorial; cytokine; dextran sulfate sodium induced colitis; experimental study; in vivo; insight; interleukin 20; interleukin-19; member; murine colitis; mutant; novel; pharmacologic; pleiotropism; receptor; repaired; response; therapeutic evaluation; tool; transcriptome sequencing; treatment strategy; tumor; tumor initiation; tumor progression; tumorigenesis; variant of interest

Robert A. Saxton | K22 (PAR-18-467) | Project Summary / Abstract Although inflammation is essential for protecting organisms against infection, excessive or chronic inflammation is also associated with an increased risk of certain cancers. This is particularly true at epithelial barriers such as the colonic mucosa in the gastrointestinal (GI) tract, which are in frequent contact with the external environment and therefore particularly susceptible to damaging inflammatory responses. Indeed, over 20% of patients with inflammatory bowel disease (IBD) will go on to develop colitis-associated cancer (CAC). Moreover, most therapeutic options for autoinflammatory diseases like IBD involve the use of immunosuppressive drugs, which may also increase tumor incidence due to reduced immunosurveillance. An alternative approach is to exploit natural mechanisms of tissue protection and repair in order to reduce tumor-promoting inflammation without suppressing anti-tumor immune responses. Recently, several members of the IL-20 cytokine family have been shown to be upregulated in both IBD and GI cancers, but their functional roles in these contexts are not fully understood. This includes the cytokines IL-19, IL-20, and IL-24, all of which signal through the shared receptor subunit IL-20Rβ. However, whether this upregulation drives disease pathology or reflects a beneficial but insufficient homeostatic response remains unclear. This is largely due to the combinatorial and interconnected nature of receptor sharing within this family, resulting in a high degree of functional pleiotropy and redundancy that hinders experimental interrogation of these pathways. In this project, we will employ structure-guided protein engineering to deconvolute the pleiotropic functions of IL-20Rβ ligands in inflammation-associated colon cancer. We will first use a combination of directed evolution and structure-based rational protein design to develop a pharmacological toolkit, comprising IL-20 receptor agonists and antagonists with altered receptor specificities, allowing us to selectively modulate the activity of individual IL-20Rβ ligands. We will then use these tools in vivo to probe the effect of these engineered proteins in the development, progression, and gene expression changes over the course of colitis induction and tumor progression, using the well-established AOM/DSS mouse model of CAC. Together, these studies will provide important insights into the protective and pathogenic functions of distinct IL-20Rβ ligands in CAC, while also directly testing the therapeutic potential of our engineered cytokine variants in the prevention of inflammation associated cancer.

罗伯特·A·萨克斯顿| K22（PAR-18-467）|项目摘要 /摘要 尽管炎症对于保护生物免受感染，过度或慢性是至关重要的 炎症也与某些癌症的风险增加有关。上皮尤其如此 胃肠道（GI）中的结肠粘膜等障碍，经常与 外部环境，因此尤其容易受到损害炎症反应的影响。确实，结束了 20％的炎症性肠病患者（IBD）将继续发展与结肠炎相关的癌症（CAC）。 此外，诸如IBD之类的自身炎症性疾病的大多数治疗选择都涉及 免疫抑制药物，这也可能增加由于免疫监测降低而增加肿瘤的发病率。 另一种方法是利用组织保护和修复的自然机制，以便 减少促进肿瘤的炎症，而无需抑制抗肿瘤免疫反应。最近，几个 IL-20 Cytokine家族的成员已显示在IBD和GI癌症中已更新 在这些情况下的功能角色尚未完全理解。这包括细胞因子IL-19，IL-20和IL-24， 所有这些通过共享受体亚基IL-20Rβ发出信号。但是，这种上调是否驱动 疾病病理或反映了有益但不足的稳态反应尚不清楚。这很大程度上 由于接收器共享该家庭内部共享的组合和相互联系的性质，因此很高 功能性多效性和冗余的程度，阻碍了这些途径的实验询问。 在这个项目中，我们将采用结构引导的蛋白质工程来解宣告多效性 IL-20Rβ配体在炎症相关结肠癌中的功能。我们将首先使用 定向进化和基于结构的理性蛋白质设计，以开发药物工具包，完成 IL-20受体激动剂和具有改变受体规格的拮抗剂，使我们能够选择性调节 单个IL-20Rβ配体的活性。然后，我们将使用这些工具在体内探测这些效果 在结肠炎过程中的发育，进展和基因表达中的工程蛋白质变化 使用良好的CAC的AOM/DSS小鼠模型，诱导和肿瘤进展。在一起，这些 研究将提供对不同IL-20Rβ配体在受保护和致病功能中的重要见解 CAC，同时还直接测试了我们工程细胞因子变体的治疗潜力 炎症相关的癌症。