权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Synthetic morphogenesis to recapitulate multicellular airway branching patterns

合成形态发生来概括多细胞气道分支模式

基本信息

批准号：
10606897
负责人：
Ian S Kinstlinger
金额：
$ 6.95万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
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：
2023-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10606897
关键词：
3-Dimensional Anatomy Architecture Area Biochemical Biological Biological Models Cell Communication Cell Proliferation Cell model Cells Cellular Morphology Cellular Structures Clinical Treatment Coculture Techniques Communication Complex Comprehension Computer Models Coupled Cues Development Developmental Biology Devices Diffuse Pattern Diffusion Distal Embryo Engineering Environment Epithelium Experimental Designs Experimental Models Feedback Fractals Functional Regeneration Gene Expression Generations Goals Higher Order Chromatin Structure Human In Situ Investigation Kidney Knowledge Light Lung Lung diseases Mammary gland Maps Mathematics Measures Mesenchymal Mesenchyme Microfluidics Microscopy Modeling Morphogenesis Morphology Mus Nature Outcome Pancreas Paracrine Communication Pathway interactions Pattern Physiological Population Positioning Attribute Process Program Development Reaction Regenerative Medicine Reporter Repression Resolution Reverse engineering Scheme Signal Pathway Signal Repression Signal Transduction Stereotyping Structure Structure of parenchyma of lung Synthetic Genes Testing Therapeutic Tissue Engineering Tissues Training Trees Work biliary tract cell type cellular imaging design experience experimental study in vitro Model inducible gene expression insight intercellular communication interest knockout gene lung development lung regeneration migration morphogens network architecture novel optogenetics progenitor programs receptor regenerative regenerative therapy response self assembly small molecule spatiotemporal stem cells synthetic biology synthetic construct tool

项目摘要

Abstract The bronchial network of the human lung is a tree-like structure comprising over 20 generations of dichotomous branching; yet, the signaling basis for how this elaborate network is patterned has remained an enduring mystery. This represents not only a fundamental knowledge gap in developmental biology, but also a limiting factor for developing regenerative therapies to counter lung disease. While there are several plausible hypotheses as to how this patterning mechanism could operate, testing them has proven beyond the limits of classical gene knock- out experiments and other traditional reverse engineering approaches due to the complex signaling crosstalk found in situ. In this proposal, I will unify a classic experimental model in lung development (mesenchyme-free culture of distal lung epithelium) with state-of-the-art synthetic cell-cell signaling tools in order to map the design space for branch-patterning mechanisms. Working in a state-of-the-art Biological Design Center with a team of experts in mammalian synthetic biology and lung development, I will employ a “build-to-understand” approach wherein I construct synthetic cell populations that can either communicate with ex vivo tissues using endogenous signaling networks, or communicate with other synthetic cells using signaling pathways orthogonal to any found in nature. I will use these engineered cells to recapitulate an activation/repression feedback cycle which is thought to be vital in lung branching morphogenesis. By manipulating cell-cell communication, I will be able to isolate the fundamental design principles that govern how activation and repression signals between cells can manifest in higher- order structures. Furthermore, by decoupling specific signaling axes from their larger developmental context, and by performing high-resolution, time-lapse imaging of cell fate, I will be uniquely positioned to interrogate tissue pattern- ing mechanisms with unprecedented control. I hypothesize that reciprocal activation and repression between two cell types can give rise to a broad range of multicellular patterning outcomes depending on additional feedback loops and initial conditions. To test this hypothesis, I will explore the how the morphology and topol- ogy of multicellular patterns can be tuned by manipulating the signaling interactions between them. My overarching hypothesis is based on the predictions of previous computational models of branching morphogenesis via reaction- diffusion patterning, so I will use those predictions, and this theoretical framework, to guide my experimental designs. To assess whether synthetic signaling by engineered cells could also be a tractable approach for generating regen- erative lung tissue, I will further interrogate a 3D in vitro model where cell-cell signaling occurs exclusively through synthetic morphogens and receptors. Taken together, these studies will provide fundamental insights into how complex anatomical structures can be encoded in relatively simple signaling schemes which are executed locally between cells. Analysis of the resulting branch patterns is also expected to inspire a new paradigm for har- nessing synthetic cell-cell signaling to guide and direct the morphogenesis of therapeutically relevant cell types into tissue-specific architectures for regenerative medicine.

摘要