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Probing mesoscale receptor organization in T cell signaling with DNA origami

用 DNA 折纸探测 T 细胞信号传导中的中尺度受体组织

基本信息

批准号：
10726455
负责人：
Shawn M Douglas
金额：
$ 20.19万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-19 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10726455
关键词：
3-Dimensional Address Adoptive Cell Transfers Affect Antibodies Antigen Presentation Antigen-Presenting Cells Autoimmune Diseases Binding Biochemistry Biological Process Cell Signaling Process Cell Therapy Cell model Cell surface Cells Cues DNA Dependence Development Diabetes Mellitus Disease Engineering Exclusion Foundations Goals Health Benefit Height Human Immune signaling Immunotherapy Interleukin-2 Knowledge Lateral Learning Ligands Linker DNA Malignant Neoplasms Mediating Nanostructures Nanotechnology Nucleotides Pathway interactions Patients Pattern Peptide/MHC Complex Phosphotransferases Positioning Attribute Process Production Public Health Reagent Resolution Role Signal Pathway Signal Transduction Signaling Molecule Single-Stranded DNA Structure Surface T cell regulation T cell therapy T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Therapeutic Work cancer immunotherapy cancer therapy cell behavior engineered T cells extracellular feasibility testing immunological synapse immunological synapse formation insight interest light microscopy manufacture migration nanopattern nanoscale novel programmed cell death protein 1 receptor scaffold stoichiometry success tool two-dimensional

项目摘要

PROJECT SUMMARY Understanding and manipulating cell signaling processes is crucial for adoptive cell therapies (ACT), which show significant promise in treating diseases such as cancer and diabetes. Many of the current challenges in manufacturing these therapeutics are related to our lack of control over ex vivo T cell activation. Though tremendous progress has been made in understanding how extracellular signaling cues influence intracellular states, our understanding of detailed mechanisms governing these processes is incomplete. Mounting evidence suggests that cell signaling is regulated by the physical arrangement of signaling structures at the surface of cells. However, determining how the spatial arrangement of signaling structures guides cell behavior is very difficult due to the nanoscale size of these structures, which is below the resolution limit of traditional light microscopy. This study will provide crucial information towards elucidating the role of spatial organization in T cell regulation, as well as test the feasibility of novel tools to study and manipulate structures on the nanoscale. Our objective is to determine how 3D spatial arrangements of signaling molecules affect T cell behavior. To do so, we will use DNA origami nanostructures to arrange ligands into nanoscale 3D patterns, then present these patterned ligands to T cells and characterize signaling dynamics, we will also assess ACT-relevant parameters such as T cell proliferation rate and IL-2 secretion. Our rationale is that by defining the relationship between ligand arrangement and T cell signaling, we will better understand how the organization of signaling molecules at the cell surface regulates intracellular pathways, which will guide the development of optimized reagents for efficient ex vivo T cell activation. This project will leverage nanotechnology, biochemistry, and cell to accomplish three Specific Aims: 1) determine the relationship between extracellular receptor kinase dynamics and 3D stimulatory ligand arrangement, 2) determine the spatial dependence of inhibitory receptors on T cell activation, and 3) create patterned T cell signaling reagents that can trigger ex vivo primary T cell activation. We will define the relationship between the spatial organization of signaling molecules and intracellular pathways, and in establishing the foundation for nanopatterned immunotherapy reagents. This knowledge will allow us to more deeply understand the mechanisms underlying T cell activation and differentiation, enabling efficient and efficacious manufacturing of cell therapies for cancer, diabetes, and other diseases.

项目总结