New tools for tracking single cells in vivo

体内追踪单细胞的新工具

• 批准号: 10248540
• 负责人: Guillem Pratx
• 金额: $ 62.01万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248540
• 关键词: 3-Dimensional; Algorithms; Animal Model; Basic Science; Biological; Biological Process; Biomedical Research; Blood Circulation; Cell Cycle Kinetics; Cell Therapy; Cell Transplantation; Cells; Clinical; Clinical Research; Contrast Media; Development; Diabetes Mellitus; Disease; Embryonic Development; Engineering; Experimental Models; Felis catus; Genetic; Goals; Health; Heart Ventricle; Heart failure; Hematopoiesis; Human; Human body; Image; Imaging Device; Immunity; Immunotherapy; In Vitro; Individual; Injections; Investigation; Kinetics; Label; Left; Link; Lipids; Liver; Location; Measurement; Measures; Melanoma Cell; Metastatic Melanoma; Methods; Microfluidic Microchips; Microfluidics; Modeling; Molecular; Molecular Profiling; Mus; Neoplasm Metastasis; Organ; Outcome; Output; Pathology; Patients; Pattern; Phase; Phenotype; Physiological Processes; Population; Positioning Attribute; Positron-Emission Tomography; Pre-Clinical Model; Predictive Factor; Process; Proteins; Radioactivity; Radiolabeled; Reporter; Reproducibility; Role; Route; Signal Transduction; Silicon Dioxide; Surface; System; Technology; Testing; Time; Toxic effect; Tracer; Translating; Translational Research; Translations; Treatment Protocols; Validation; cell motility; computerized tools; design; human imaging; imaging modality; improved; in vivo; insight; migration; molecular imaging; molecular phenotype; nanoparticle; novel; novel strategies; novel therapeutics; pre-clinical; pre-clinical research; predicting response; programs; radiotracer; receptor expression; reconstruction; spatiotemporal; stem cell migration; stem cell therapy; survival prediction; tool; trafficking; treatment optimization

Abstract This project will develop a new pipeline for tracking the migration of single cells in vivo at the whole-body level. Cell migration is a crucial biological process involved in the pathology and treatment of some of the world’s most intractable diseases. Stem cell therapy and immunotherapy, for instance, are emerging as viable treatments for conditions previously thought incurable, such as heart failure and diabetes. Unfortunately, cell tracking methods remain inadequate to fully capitalize on these recent advances. Currently, cell tracking relies on imaging the distribution of a specific population of cell through a contrast agent, which is either directly affixed to the cells or targeted towards an engineered reporter protein. This approach precludes precise measurement of cell circulation kinetics or migration routes. Furthermore, due to efflux and non-specific retention, the distribution of the contrast agent does not necessarily match the underlying distribution of cells. In view of these challenges, we consider a novel approach that has the potential to revolutionize cell tracking. While current methods aim to track bulk populations of cells, we hypothesize that novel biological insight may be gained by tracking cells individually, in small numbers, with unprecedented temporal and spatial accuracy. We will pursue the development of CellGPS, a method capable of tracking the 3D position of individual cells continuously as these cells migrate through the body of a living subject. To accomplish this goal, we rely on a previously developed algorithm that can extract the position of a moving cell directly from the raw list-mode output of a positron emission tomography (PET) scanner. PET is the most sensitive imaging modality available for whole-body human imaging and, therefore, the ideal imaging modality for this project. Building on extensive preliminary studies, we plan to pursue the following four specific aims: (1) develop a rapid, safe and robust strategy for radiolabeling cells; (2) design and build a novel microfluidics pipeline to molecularly profile and isolate single cells for in vivo tracking; (3) evaluate single-cell tracking as a readout of cell dissemination in an experimental model of metastatic melanoma; and (4) explore translation of this technology to human imaging scanners. This project is expected to generate a positive impact for biomedical research both in the pre-clinical and clinical setting. For instance, single-cell tracking could be used to determine the spatiotemporal kinetics of cell migration during the earliest phase of the metastatic cascade. The method could also help determine the dynamic distribution of cells after transplantation for cell-based therapy, which could help predict response and optimize treatment regimen. This project will achieve critical milestones towards routine and reproducible tracking of single cells in vivo using PET.

摘要