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体免受感染至关重要，但过度或慢性炎症 炎症还与某些癌症的风险增加有关，在上皮细胞中尤其如此。 例如胃肠道 (GI) 中的结肠粘膜，经常与食物接触 外部环境因此特别容易受到破坏性炎症反应的影响。 20% 的炎症性肠病 (IBD) 患者将继续发展为结肠炎相关癌症 (CAC)。 此外，大多数针对 IBD 等自身炎症性疾病的治疗选择都涉及使用 免疫抑制药物，由于免疫监视降低，也可能增加肿瘤发病率。 另一种方法是利用组织保护和修复的自然机制 最近，一些研究发现，在不抑制抗肿瘤免疫反应的情况下，可以减少促进肿瘤的炎症。 IL-20 细胞因子家族成员已被证明在 IBD 和胃肠道癌症中表达上调，但它们的 这些情况下的功能作用尚未完全了解，其中包括细胞因子 IL-19、IL-20 和 IL-24。 所有这些都通过共享受体亚基 IL-20Rβ 发出信号，但是这种上调是否会驱动。 疾病病理学或反映有益但不充分的稳态反应，这在很大程度上仍不清楚。 由于该家族内受体共享的组合和相互关联的性质，导致高 功能多效性和冗余的程度阻碍了这些途径的实验研究。 在这个项目中，我们将采用结构引导的蛋白质工程来解卷积多效性 IL-20Rβ 配体在炎症相关结肠癌中的功能我们将首先使用以下组合。 定向进化和基于结构的合理蛋白质设计来开发药理学工具包，包括 IL-20 受体激动剂和拮抗剂具有改变的受体特异性，使我们能够选择性地调节 然后，我们将在体内使用这些工具来探究各个 IL-20Rβ 配体的活性。 结肠炎发展、进展和基因表达变化中的工程蛋白 诱导和肿瘤进展，使用完善的 AOM/DSS 小鼠 CAC 模型。 研究将为不同 IL-20Rβ 配体的保护和致病功能提供重要见解 CAC，同时还直接测试我们的工程细胞因子变体在预防中的治疗潜力 炎症相关的癌症。