Robust Control of the Stem Cell Niche

干细胞生态位的稳健控制

• 批准号: 9900838
• 负责人: Xiling Shen
• 金额: $ 56.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900838
• 关键词: 3D Print; ATAC-seq; Abdomen; Ablation; Address; Animals; Architecture; Area; Biological; CRISPR/Cas technology; Cell Fate Control; Cell Lineage; Cell division; Cells; Communities; Devices; Disease; Electrical Engineering; Embryo; Engraftment; Enteric Nervous System; Future; Goals; Heterogeneity; Homeostasis; Human; Immune Tolerance; Immunocompetent; Inflammation; Inflammatory; Intestines; Lasers; MicroRNAs; Modeling; Mus; Natural regeneration; Process; Regenerative Medicine; Research; Resolution; Stress; Technology; Testing; Thymus Gland; Time; Tissues; Untranslated RNA; Vision; base; cell motility; chemokine; design; disorder risk; epigenetic profiling; epigenome editing; epigenomics; graphene; insight; intestinal epithelium; intravital imaging; man; new technology; novel; scaffold; segregation; sensor; spatiotemporal; stem cell niche; stem cells; tool; 3D Print; ATAC-seq; Abdomen; Ablation; Address; Animals; Architecture; Area; Biological; CRISPR/Cas technology; Cell Fate Control; Cell Lineage; Cell division; Cells; Communities; Devices; Disease; Electrical Engineering; Embryo; Engraftment; Enteric Nervous System; Future; Goals; Heterogeneity; Homeostasis; Human; Immune Tolerance; Immunocompetent; Inflammation; Inflammatory; Intestines; Lasers; MicroRNAs; Modeling; Mus; Natural regeneration; Process; Regenerative Medicine; Research; Resolution; Stress; Technology; Testing; Thymus Gland; Time; Tissues; Untranslated RNA; Vision; base; cell motility; chemokine; design; disorder risk; epigenetic profiling; epigenome editing; epigenomics; graphene; insight; intestinal epithelium; intravital imaging; man; new technology; novel; scaffold; segregation; sensor; spatiotemporal; stem cell niche; stem cells; tool

Overview The interdisciplinary lab focuses an overarching question: how biological controls manage heterogeneity and achieve robustness, and how subversion of such mechanisms heightens risk for disease. To address this question, the lab studies fundamental mechanisms and develops new technology to probe such processes in live animals at high spatiotemporal resolution: 1) The lab has discovered that non-coding RNA (ncRNA) such as long non-coding RNA (lncRNA) and microRNA can initiate asymmetric cell division and limit plasticity. Not essential for healthy tissue, ncRNA can be triggered to turn on asymmetric division to safeguard tissue integrity during inflammation-induced reparative regeneration. 2) The lab discovered that fast- and slow-cycling intestinal stem cells can directly interconvert via asymmetric division, representing an optimal survival strategy for the tissue. 3) To address the limitation of current engraftment models, the lab developed a novel chemokine-targeting technology to engraft human cells into immunocompetent mouse hosts by manipulating cell migration via embryonic thymus to build central immune tolerance. 4) A new device integrating an abdominal window, a 3D-printed scaffold, and a transparent graphene sensor has been designed to demonstrate live recording of the enteric nervous system for the first time. Goals In the next five years, the lab will explore three areas: Goal 1. Elucidating the ncRNA mechanisms that regulate asymmetric division and safeguard tissue integrity, e.g., to understand their mechanism of asymmetric segregation and to identify such lncRNAs and microRNAs in a systematic way. Goal 2. Understanding the spatiotemporal dynamics of the intestinal stem cell niche using intravital imaging, laser ablation, and multiscale stochastic modeling. Goal 3. Epigenetic profiling and reprogramming of intestinal cell lineages using ATAC-seq and CRISPR-Cas9- based epigenome editing. Vision With a background in electrical engineering, the PI has always been intrigued by the ability of biological circuits to perform robust functions with very imprecise components and seemingly messy architectures, in contrast to man-made electrical circuits which rely on precise devices and carefully laid-out designs. The proposed study attempts to deepen our understanding of tissue homeostasis and highlights the sophistication of underlying biological circuitry in terms of dynamics and robustness. The lab will also develop new tools for the research community to ask the kind of questions that are impossible right now. The study will provide new insight into disease conditions and contribute to future regenerative medicine.

概述跨学科实验室重点关注一个总体问题：生物控制如何管理 异质性和实现鲁棒性，以及这种机制的颠覆如何增加疾病的风险。到 解决这个问题，实验室研究基本机制，并开发了新技术来探究此类 高时空分辨率的活动物中的过程： 1）实验室发现非编码RNA（NCRNA），例如长非编码RNA（LNCRNA）和microRNA 可以引发不对称的细胞分裂并限制可塑性。对于健康组织不是必需的，可以触发NCRNA 在炎症引起的修复再生过程中，打开不对称分裂以保护组织完整性。 2）实验室发现快速和慢速肠道干细胞可以直接通过不对称互连 分裂，代表组织的最佳生存策略。 3）为了解决当前植入模型的局限性，实验室开发了一种新型的趋化因子靶向 通过操纵细胞迁移的技术，将人类细胞植入免疫能力的小鼠宿主的技术 胚胎胸腺建立中央免疫耐受性。 4）一个集成腹部窗口，3D打印脚手架和透明石墨烯传感器的新设备 旨在首次展示肠神经系统的现场记录。 在未来五年的目标中，实验室将探索三个领域： 目标1。阐明调节不对称分裂和保护组织完整性的NCRNA机制， 例如，了解它们的不对称隔离机制，并在 一种系统的方式。 目标2。了解肠干成像的肠干细胞生态位时空动力学， 激光消融和多尺度随机建模。 目标3。使用ATAC-SEQ和CRISPR-CAS9-的肠细胞谱系的表观遗传分析和重编程 基于表观基因组编辑。 具有电气工程背景背景的视觉，PI始终对生物学的能力感兴趣 通过非常不精确的组件和看似混乱的体系结构执行强大功能的电路， 与依靠精确设备和精心布置设计的人造电路形成对比。这 拟议的研究试图加深我们对组织稳态的理解，并突出了 在动力学和鲁棒性方面的基本生物回路。该实验室还将为 研究社区问现在​​不可能的问题。该研究将提供新的见解 进入疾病状况并有助于未来再生医学。