| 项目编号: | 1651645
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| 项目名称: | CAREER: Engineering Human CNS Morphogenesis Ex Vivo: Spinal Cord |
| 作者: | Randolph Ashton
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| 承担单位: | University of Wisconsin-Madison
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| 批准年: | 2017
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| 开始日期: | 2017-07-01
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| 结束日期: | 2022-06-30
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| 资助金额: | 546609
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| 资助来源: | US-NSF
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| 项目类别: | Standard Grant
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| 国家: | US
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| 语种: | 英语
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| 特色学科分类: | Engineering - Chemical, Bioengineering, Environmental, and Transport Systems
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| 英文关键词: | engineer human neural organoid
; morphogenesis
; spinal cord grey matter tissue
; cns model
; spontaneous morphogenesis process
; tissue engineering research
; student
; engineer human organoid
; human developmental biology
; project
; human central nervous system
; applicable morphogenesis engineering principle
; spinal cord injury research
; engineering human organoid morphogenesis
; composite spinal cord organoid
; cns-like neuronal circuitry
; human organoid morphogenesis
; cns development
; humanoid experimental platform
; human pluripotent stem cell
; engineering human cord organoid
; future hpsc-based tissue engineering industry
; spinal cord grey matter architecture
; spinal cord
; spinal cord tissue
; human psc-derived organoid
; modeling human biology
; spinal cord organoid exemplar
; method
; degenerative spinal cord disease
; organoid
; engineer biomimetic human tissue
; human spinal cord
; engineering parameter
; stem cell-based tissue engineering
; hypothesis
; human spinal cord organoid
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| 英文摘要: | PI: Ashton, Randolph S.
Proposal #: 1651645
The recently observed ability of combinations of human pluripotent stem cells (hPSCs) to spontaneously transform in vitro into "cerebral organoids" containing diverse brain tissues suggests the possibility that organoids can be engineered ex vivo to generate brain and spinal cord tissues with structure, composition and function (including neural circuits) that can mimic many features of the human Central Nervous System (CNS). The availability of controlled ex vivo CNS models can lead to platforms for 1) investigating human developmental biology and physiology, 2) investigating degenerative diseases and traumatic injury, 3) enhanced drug screening and personalized medicine and 4) eliminating the need for questionably relevant animal studies. The goal of this project is to develop methods for engineering human cord organoids displaying spinal cord grey matter architecture and CNS-like neuronal circuitry. Success could lead to a paradigm shift relative in spinal cord injury research and drug screening. The proposed methods can be implemented to engineer diverse neural, heart, and gut organoids. The education and outreach plan includes: 1) development of a comprehensive "Stem cell-based Tissue Engineering & Morphogenesis (STEM)" website to serve as an educational resource for BME courses and middle and high school teachers and as a site for sharing research findings, 2) outreach programs designed to expose underrepresented minority (URM) students, including at elementary and middle school levels, to STEM experiences and 3) creation of a live "Building a Human Spinal Cord" exhibit to engage the public in stem cell and tissue engineering research.
This project will use innovative culture platforms to develop standardized methodologies for reproducibly engineering human spinal cord organoids, chosen due the spinal cord's comparatively simplified tissue morphology. The Research Plan is organized under 3 objectives with related hypotheses: 1) Engineer human neural organoids with posterior neural tube (PNT) tissue structure--The hypothesis that spatial control of organoid morphology at developmental length scales can induce biomimetic tissue structure will be tested using a novel molding technology to develop a standardized methodology for engineer annular tubes of polarized, hPSC-derived neural stem cells (hNSCs), which is mimetic of early PNT structure, 2) Engineer human neural organoids with dorsoventral (D/V) cytoarchitecture mimetic of spinal cord grey matter tissue--The hypothesis that exogenous morphogen gradients can be applied to instruct biomimetic cellular composition and tissue cytoarchitecture within organoids will be tested using novel "Stamp-On" microfluidics to generate analogous morphogen gradients and investigate whether they can recapitulate D/V patterning of biomimetic cellular composition and cytoarchitecture within cylindrical hNSC organoids and 3) Engineer human neural organoids with rostrocaudal (R/C) cytoarchitecture mimetic of spinal cord grey matter tissue--The hypothesis that directed assembly of neural organoid tissues can induce formation of biomimetic neural will be tested by using organoids generated from cervical, thoracic, and lumbar hNSCs and testing whether their directed assembly yields a composite spinal cord organoid with biomimetic R/C tissue cytoarchitecture and functional neuronal circuitry. The 4th objective is to promote development of a diverse workforce for future hPSC-based tissue engineering industries by integrating a multifaceted approach for inspiring and educating the general public and students, especially underrepresented minorities. Though Human PSC-derived organoids possess tremendous possibilities for modeling human biology and physiology, their utility is limited by a lack of control over their spontaneous morphogenesis processes, which produces random organoid structure and composition. Using a spinal cord organoid exemplar, this project will develop novel tools and methodologies for engineering human organoid morphogenesis at the micro-to-millimeter scale. Instructing reproducible ex vivo morphogenesis at this scale is critical for developing advanced biomanufacturing processes to produce functional, biomimetic tissues and organs. Engineering parameters identified as critical to instructing emergence of biomimetic 3-D spinal organoids could elucidate broadly applicable morphogenesis engineering principles and provide new insights into CNS development and disease. The tools and knowledge generated will significantly advance scientists' ability to engineer biomimetic human tissues, specifically providing the most humanoid experimental platform to date for investigating degenerative spinal cord diseases and traumatic injury. The proposed tools and methods are designed for simplicity, thus can be broadly disseminated and implemented for engineer human organoids. Captivating data and explanations of human organoid morphogenesis will be curated as an online educational resource and introduced to the general public and students to promote political support, interests, and workforce development. |
| 资源类型: | 项目
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| 标识符: | http://119.78.100.158/handle/2HF3EXSE/89785
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| Appears in Collections: | 全球变化的国际研究计划
科学计划与规划
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| Recommended Citation: | |
Randolph Ashton. CAREER: Engineering Human CNS Morphogenesis Ex Vivo: Spinal Cord. 2017-01-01.
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