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

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.

概述跨学科实验室关注一个首要问题：生物控制如何管理 异质性并实现稳健性，以及这种机制的颠覆如何增加疾病风险。到 为了解决这个问题，实验室研究了基本机制并开发了新技术来探测此类问题 高时空分辨率下活体动物的过程： 1）实验室发现长链非编码RNA（lncRNA）和microRNA等非编码RNA（ncRNA） 可以启动不对称细胞分裂并限制可塑性。 ncRNA 对健康组织不是必需的，可以被触发 打开不对称分裂以在炎症诱导的修复再生过程中保护组织完整性。 2）实验室发现快循环和慢循环肠道干细胞可以通过不对称直接相互转化 分裂，代表组织的最佳生存策略。 3）为了解决当前移植模型的局限性，实验室开发了一种新型趋化因子靶向药物 通过操纵细胞迁移将人类细胞移植到具有免疫活性的小鼠宿主中的技术 胚胎胸腺建立中枢免疫耐受。 4）集成腹窗、3D打印支架和透明石墨烯传感器的新装置 旨在首次演示肠神经系统的实时记录。 目标 未来五年，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，了解它们的不对称分离机制并识别此类 lncRNA 和 microRNA 一种系统的方式。 目标 2. 使用活体成像了解肠道干细胞生态位的时空动态， 激光烧蚀和多尺度随机建模。 目标 3. 使用 ATAC-seq 和 CRISPR-Cas9 对肠道细胞谱系进行表观遗传分析和重编程 基于表观基因组的编辑。 愿景 具有电气工程背景的 PI 一直对生物的能力很感兴趣 电路以非常不精确的组件和看似混乱的架构执行强大的功能， 与依赖精密设备和精心布局设计的人造电路形成鲜明对比。这 拟议的研究试图加深我们对组织稳态的理解，并强调 潜在的生物电路在动力学和鲁棒性方面。该实验室还将开发新工具 研究界提出目前不可能的问题。该研究将提供新的见解 深入了解疾病状况并为未来的再生医学做出贡献。