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Sensing and modulating the chemokine environment with synthetic cells

用合成细胞感知和调节趋化因子环境

基本信息

批准号：
10566980
负责人：
Allen Po-Chih Liu
金额：
$ 19.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2023-08-21 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566980
关键词：
Address Architecture Atherosclerosis Binding Biological Models Biology Biomedical Research Biosensor CCL21 gene CXCR4 gene Cells Chemotaxis Complex Custom Development Disease Encapsulated Engineering Environment Fibroblasts Future G-Protein-Coupled Receptors Growth Factor Heterogeneity Human Hydrogels Imaging technology In Situ In Vitro Intervention Ligands Lipid Bilayers Malignant Neoplasms Mammalian Cell Measures Mediating Methods Microfilaments Molecular Monitor Movement Neoplasm Metastasis Nerve Degeneration Normal Cell Normal tissue morphology Output Pathologic Pathway interactions Peptide Hydrolases Pharmacologic Substance Phosphotransferases Physiological Physiology Proliferating Receptor Signaling Regenerative Medicine Reporter Reporting Research Research Personnel Signal Transduction Site Specificity Stromal Cell-Derived Factor 1 System Testing Therapeutic Time Tissues Vesicle Visualization Work cell behavior cell motility cell type cellular engineering cellular imaging chemokine chemokine receptor clinical translation cytokine design imaging modality improved in vivo innovation mammary migration new technology notch protein novel novel therapeutic intervention prevent quantitative imaging real time monitoring receptor reconstitution recruit regenerative therapy response source localization synthetic biology targeted agent tissue repair tool tool development trafficking

项目摘要

Project Summary Gradients of chemokines control physiologic trafficking of multiple cell types, and many of these same chemokines drive multiple diseases, including cancer, atherosclerosis, and neurodegeneration. Controlling chemokine gradients also offers novel opportunities to improve recruitment of therapeutic cells to target sites for regenerative medicine. Critical functions of chemokines and chemokine receptors in biomedicine has motivated ongoing development of new pharmaceutical agents regulating these pathways. However, clinical translation of compounds targeting chemokine signaling remains slow, due in part to unresolved basic questions about how local gradients of chemokines control cell migration, particularly in diseased tissues with loss of normal tissue architecture. While local gradients of chemokines are recognized as key determinants of cell movement, methods to measure or manipulate the chemokine environment immediately adjacent to cells remain limited. The objective of this proposal is to develop and utilize synthetic cells as a synthetic biology tool to manipulate the chemokine environment that will help address how local, cell-adjacent chemokine gradients steer chemotaxis of cells. Specifically, we will focus on two chemokine receptor pathways, CXCL12-CXCR4 and CCL21-CCR7, strongly associated with progression of several common diseases and promising targets for cell-based regenerative therapies. Synthetic cells can be engineered de novo from the bottom-up with specialized functions, including chemokine secretion. Synthetic cells are not alive, do not grow or divide, and may be a safer alternative to use in future in vivo applications. Leveraging recent synthetic biology developments in engineered mammalian and synthetic cells, synthetic cells with custom input-output relationship will be constructed. We will engineer synthetic cells to detect local concentrations of a specific chemokine, allowing real-time monitoring of chemokine gradients. We also will design synthetic cells that upon direct interaction with a living cell, respond by secreting a chemokine to disrupt the chemotactic gradient presented to a living cell. These tools will enable us to understand how local concentrations of a chemokine regulate signaling and movement of living cells. The proposed work consists of two specific aims: 1) To develop synthetic cells that can report local chemokine concentrations; and 2) To develop synthetic cells that modulate the chemokine environment to regulate chemotaxis. The proposed research is significant as it applies established synthetic biology concepts in mammalian cells to synthetic cells, filling a fundamental gap in tool development that has prevented complete understanding of chemotaxis in complex environments. The work will also have a lasting impact that opens the door for potential new interventions using engineered synthetic cells to manipulate local chemokine profiles specifically and controllably for therapy in multiple disease settings.

项目总结