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Synthetic gene sensors and effectors to redirect organoid development

合成基因传感器和效应器可重定向类器官的发育

基本信息

批准号：
10397569
负责人：
Calin Belta
金额：
$ 64.96万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397569
关键词：
3-Dimensional Blood Vessels Cadherins Cell Communication Cell Differentiation process Cell physiology Cells Classification Communication Complex Computational Technique Computer Models Computer Simulation Development Developmental Process Drug Screening Endoderm Engineering Feedback Gene Expression Generations Genes Genetic Genetic Transcription Growth Factor Guide RNA Hematopoiesis Human Image Individual Investigation Lead Liver Logic Machine Learning Mesoderm Methods Modeling Monitor Organoids Outcome Output Pattern Phenotype Plant Roots Play Population Probability Process Property Proteins Protocols documentation Psychological reinforcement Regenerative Medicine Reporter Reporting Reproducibility Role Specific qualifier value Stromal Cells Structure Switch Genes Synthetic Genes System Techniques Therapeutic Time Tissue Engineering Tissues Training Tube Visual base cell type computing resources control theory design engineering design extracellular gene regulatory network induced pluripotent stem cell information processing innovation insight mathematical model operation personalized medicine precision drugs programs self assembly self organization sensor single-cell RNA sequencing stem cell population synthetic biology three dimensional structure tool

项目摘要

Project Summary Human induced pluripotent stem cell (hiPSC)-derived organoids hold great promise for tissue engineering and personalized drug screening, but obtaining the desired multicellular organization and function from these systems is usually performed in an ad hoc fashion without forward design specification. Recently, we reported successful liver bud formation containing stromal cells, vascular tube-like structures and hematopoiesis-like processes by synthetically inducing diversity in GATA6 expression from a single hiPSC population. This accomplishment suggests that expanding circuit logic operations to artificially control differentiation drivers at particular bifurcations in lineage specification could profoundly impact the complexity and functionality of organoids. In this project, we bring together mathematical modeling, machine learning, optimization, and innovative synthetic biology techniques to elucidate and design fundamental decision and communication rules for guiding cells into complex, heterogeneous tissues. Our overarching hypothesis is that appropriate timing and predictable stochastic control of the expression of intracellular and extracellular factors is critical for redirecting lineage choices in order to elicit desired multicellular organization from a population of differentiating cells. We will develop synthetic tools for sensing differentiation stages of iPSC-derived organoids and construct and characterize a stochastic commitment switch in an inducible reporter system. These tools will be integrated in synthetic gene circuits for engineering emergent multicellular organization through stochastic temporal control of developmental factors. The modular commitment switches developed in this project will be capable of exploring how the degree of subpopulation biasing of cell fate decisions and level of cell fate synchronization at bipotent differentiation stages impacts self-assembly and emergent multicellular organization of an organoid. Our aims - executed through a closed loop of computational and experimental investigations - will shed insight on how generalizable methods of controlled manipulation can elicit desired organoid-level emergent properties.

项目总结