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

• 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
• 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

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.

项目摘要 趋化因子的衍生物控制多种细胞类型的生理运输，并且其中许多相同 趋化因子驱动多种疾病，包括癌症、动脉粥样硬化和神经变性。控制 趋化因子梯度也提供了新的机会，以改善治疗细胞的募集， 再生医学网站。趋化因子及其受体在生物医学中的重要作用 已经促使了调节这些途径的新药剂的持续开发。然而，在这方面， 靶向趋化因子信号传导的化合物的临床转化仍然缓慢，部分原因是未解决的 关于趋化因子的局部梯度如何控制细胞迁移的基本问题，特别是在疾病中， 正常组织结构丧失的组织。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 与细胞直接相邻的细胞仍然有限。该提案的目的是开发和利用合成 细胞作为一种合成生物学工具来操纵趋化因子环境， 邻近细胞的趋化因子梯度控制细胞的趋化性。具体来说，我们将重点关注两种趋化因子 受体途径，CXCL 12-CXCR 4和CCL 21-CCR 7，与几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前途的目标。合成细胞可以是 自下而上重新设计，具有特殊功能，包括趋化因子分泌。合成 细胞不是活的，不生长或分裂，并且可能是未来体内应用中使用的更安全的替代物。 利用最近在工程化哺乳动物和合成细胞方面的合成生物学发展， 将构造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响应， 破坏呈现给活细胞的趋化梯度。这些工具将使我们能够了解 趋化因子的局部浓度调节活细胞的信号传导和运动。拟议工作 由两个具体目标组成：1）开发能够报告局部趋化因子浓度的合成细胞; 和2）开发调节趋化因子环境以调节趋化性的合成细胞。的 拟议的研究是重要的，因为它适用于哺乳动物细胞中建立合成生物学概念， 合成细胞，填补了工具开发中的一个根本空白，该空白阻碍了对 复杂环境中的趋化性这项工作也将产生持久的影响，为 使用工程合成细胞操纵局部趋化因子谱的潜在新干预措施 具体地且可控地用于多种疾病环境中的治疗。