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.

Robert A.萨克斯顿|K22（PAR-18-467）|项目总结/摘要 虽然炎症对于保护生物体免受感染是必不可少的，但过度或慢性炎症是不可或缺的。 炎症也与某些癌症的风险增加有关。这在上皮细胞中尤其如此。 屏障，例如胃肠道（GI）中的结肠粘膜，其与胃肠道（GI）中的肠粘膜频繁接触。 外部环境，因此特别容易受到破坏性炎症反应的影响。事实上，在 20%的炎症性肠病（IBD）患者将继续发展结肠炎相关癌症（CAC）。 此外，对于自身炎性疾病如IBD的大多数治疗选择涉及使用 免疫抑制药物，这也可能增加肿瘤发病率由于减少免疫监视。 另一种方法是利用组织保护和修复的天然机制， 减少促肿瘤炎症而不抑制抗肿瘤免疫应答。最近有数 IL-20细胞因子家族的成员已显示在IBD和GI癌症中上调，但它们的表达水平在IBD和GI癌症中上调。 在这些背景下的职能作用没有得到充分理解。这包括细胞因子IL-19、IL-20和IL-24， 所有这些都通过共享的受体亚基IL-20 R β进行信号传导。然而，这种上调是否会导致 疾病病理学或反映有益但不充分的稳态应答仍然不清楚。这主要是 由于该家族内受体共享的组合和相互关联的性质， 功能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，我们将采用结构导向的蛋白质工程来解卷积多效性蛋白质。 IL-20 R β配体在炎症相关结肠癌中的作用我们将首先使用 定向进化和基于结构的合理蛋白质设计，以开发药理学工具包，包括 具有改变的受体特异性的IL-20受体激动剂和拮抗剂，使我们能够选择性地调节 单个IL-20 R β配体的活性。然后，我们将在体内使用这些工具来探测这些 工程蛋白在结肠炎的发展、进展和基因表达变化过程中的作用 诱导和肿瘤进展，使用良好建立的CAC的AOM/DSS小鼠模型。所有这些 这些研究将为不同IL-20 R β配体的保护和致病功能提供重要的见解， CAC，同时也直接测试了我们的工程细胞因子变体在预防肿瘤中的治疗潜力。 炎症相关的癌症。