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Structure-based engineering of immune cytokine signaling

基于结构的免疫细胞因子信号转导工程

基本信息

批准号：
10717246
负责人：
Kenan Christopher GARCIA
金额：
$ 51.78万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717246
关键词：
3-Dimensional Address Agonist Antineoplastic Agents Architecture Award Binding Biological CD8B1 gene Cells Chemistry Complex Cryoelectron Microscopy Cytokine Receptors Cytokine Signaling Dimerization Dose Limiting Engineering G-Protein-Coupled Receptors Grant Hand Homeostasis Homo Image Immune Immune system Immunotherapeutic agent Interferons Interleukin 2 Receptor Interleukin 2 Receptor Gamma Interleukin-10 Interleukin-12 Interleukin-2 JAK1 gene JAK3 gene Janus kinase Knowledge Length Ligands Malignant Neoplasms Mediating Membrane Molecular Mus Natural Killer Cells Outcome Paint Pattern Pharmaceutical Preparations Play Property Protein Engineering Receptor Signaling Reporting Role Signal Transduction Specificity Structure Structure-Activity Relationship System T-Lymphocyte Therapeutic Toxic effect Translations Variant analog antitumor agent antitumor effect cancer immunotherapeutics cancer immunotherapy cancer therapy cell type cytokine design exhaustion extracellular fighting immunoengineering immunoregulation improved in vivo interleukin-12 receptor interleukin-21 interleukin-22 interleukin-23 leukocyte proliferation nanobodies pharmacologic pleiotropism preference receptor reconstitution stemness structural biology systemic toxicity translational barrier tumor tumor immunology

项目摘要

ABSTRACT: Immunoregulatory cytokines engage transmembrane signaling receptors in order to mediate a wide range of functions including leukocyte proliferation, differentiation, and expansion through JAK/STAT activation. Most immunoregulatory cytokines possess both redundant and distinct activities that are critical to normal immune homeostasis, but this functional pleiotropy presents a major problem for the effective use of these cytokines as immunotherapeutic cancer drugs. Cytokine pleiotropy is a consequence of different cytokine receptors being expressed on multiple different counterbalancing cell types that serves to neutralize anti-tumor actions and lead to systemic toxicity. During the prior term of this award, we gained an appreciation for the extracellular structural architectures of a spectrum of different immune cytokine complexes, including those of IL-2, IL-10, IL-12, IL-21, IL-22, IL-23, IL-27, IFN, and IFN. In this renewal application, with these structural templates in hand, in Aim 1 we focus our studies on the cytokines IL-2, IFN, and IL-12. These immune master regulators engage different but overlapping branches of the immune system, and share the issues of pleiotropy and toxicity that, if uncoupled, could lead to powerful cancer immunotherapeutic agents. We propose to “tune” signaling through structure-based cytokine engineering to attempt to create variants with decoupled pleiotropy, cell subset preferences, enhanced anti-tumor efficacies, and reduced toxicity – both alone and in combination. In Aim 2, we wish to understand the mechanistic basis for how tuned cytokines can differentially activate signaling inside the cells. Based on a recent breakthrough in our 20-year quest to solve the full-length JAK structure, we continue to pursue structural information on how cytokine binding to their receptors activates Janus Kinase (JAK) molecules, by reconstituting and imaging activated JAK homo- and heterodimers bound to both cytokine and intracellular JAKs and STATs. In this fashion, by combining structural biology, protein engineering, cell signaling, and in vivo tumor studies, we propose to obtain a complete molecular snapshot of cytokine receptor signaling from the initial engagement of ligand through the activation of intracellular signaling cascades and leverage this information for the engineering of cancer immunotherapeutics.

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