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.

项目概要趋化因子的梯度控制多种细胞类型的生理运输，其中许多细胞类型相同趋化因子会导致多种疾病，包括癌症、动脉粥样硬化和神经变性。控制趋化因子梯度还提供了新的机会来改善治疗细胞的靶向募集再生医学网站。趋化因子和趋化因子受体在生物医学中的关键功能推动了调节这些途径的新药物的持续开发。然而，针对趋化因子信号传导的化合物的临床转化仍然缓慢，部分原因是尚未解决关于趋化因子的局部梯度如何控制细胞迁移的基本问题，特别是在患病细胞中失去正常组织结构的组织。虽然趋化因子的局部梯度被认为是关键细胞运动的决定因素、测量或操纵趋化因子环境的方法紧邻细胞的区域仍然有限。该提案的目标是开发和利用合成细胞作为一种合成生物学工具来操纵趋化因子环境，这将有助于解决局部、细胞相邻的趋化因子梯度引导细胞的趋化性。具体来说，我们将重点关注两种趋化因子受体途径 CXCL12-CXCR4 和 CCL21-CCR7 与多种疾病的进展密切相关常见疾病和基于细胞的再生疗法的有希望的目标。合成细胞可以是从头开始设计，具有特殊功能，包括趋化因子分泌。合成的细胞不是活的，不会生长或分裂，并且可能是未来体内应用的更安全的替代方案。利用工程哺乳动物和合成细胞的最新合成生物学进展，合成将构建具有自定义输入输出关系的单元。我们将设计合成细胞来检测特定趋化因子的局部浓度，允许实时监测趋化因子梯度。我们也将设计合成细胞，在与活细胞直接相互作用时，通过分泌趋化因子来做出反应破坏活细胞的趋化梯度。这些工具将使我们能够了解如何趋化因子的局部浓度调节活细胞的信号传导和运动。拟议的工作包括两个具体目标：1）开发能够报告局部趋化因子浓度的合成细胞； 2) 开发调节趋化因子环境以调节趋化性的合成细胞。这拟议的研究意义重大，因为它将哺乳动物细胞中已建立的合成生物学概念应用于合成细胞，填补了工具开发中的一个根本性空白，该空白阻碍了对复杂环境下的趋化性。这项工作还将产生持久的影响，为使用工程合成细胞来操纵局部趋化因子谱的潜在新干预措施专门且可控地用于多种疾病的治疗。