CAREER: An Integrated Research and Education Program to Investigate Hypoxia and Matrix Remodeling During Stem Cell Differentiation and Lymphatic Morphogenesis

作为循环系统的重要组成部分，淋巴血管调节组织液的稳定性、膳食脂肪的吸附和免疫细胞的运输。尽管淋巴管在健康和癌症、阿尔茨海默病、肥胖和慢性伤口等疾病中发挥着重要作用，但人们对淋巴管形成的分子机制知之甚少。通过设计生物材料来控制干细胞分化，这个CAREER项目试图确定氧信号和环境信号在早期发育过程中调节淋巴管形成中的作用。最终，这项研究有望揭示淋巴生长的机制。此外，综合教育和推广计划旨在通过关注学生早期参与服务学习来激发他们对STEM领域的兴趣，从而促进各个层次的学习。该项目通过以下方式支持教育和扩大参与：(1)通过科学展览激发人们对干细胞研究的兴趣；(2)通过动手模块向中学生介绍新兴的生物材料领域；(3)通过美国国家科学基金会教师研究经验项目（RET）对高中教师和学生进行当代生物工程主题的教育。研究者的长期研究目标是利用工程原理在干细胞分化和淋巴管形态发生方面取得突破，同时将研究与未来劳动力的工程师教育和培训相结合。为了实现这一目标，本CAREER项目旨在整合研究和教育项目，致力于缺氧信号通路和基质驱动信号之间的功能相互作用的跨学科研究，这些信号通路和基质驱动信号对于干细胞分化为淋巴内皮细胞（LECs）和最终形成淋巴血管的形态发生至关重要。具体来说，需要解决的三个基本问题是：(1)在血液和淋巴网络之间的早期分离过程中，氧浓度的变化如何影响血管祖细胞进入LECs的命运？(2)基质类型（如透明质酸、胶原蛋白）和性质（如硬度、网状尺寸、降解）在体外淋巴形态发生和网络组装过程中是如何改变的？(3)在淋巴网络组装过程中，缺氧和基质驱动信号之间发生了什么功能相互作用？为了回答这些重要的问题，拟议的研究将利用跨学科的方法，涵盖从聚合物科学到干细胞和淋巴生物学的许多领域。总的来说，该项目将开发有助于刺激淋巴管生长的基础知识，实现有效和强大的细胞疗法，以及疾病和药物开发的体外模型。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

As an essential part of the circulatory system, the lymphatic vasculatures regulate stability of tissue fluid, adsorption of dietary fat, and trafficking of immune cells. Despite their important role in health and diseases such as cancer, Alzheimer's disease, obesity, and chronic wounds, little is known about the molecular mechanisms regulating lymphatic vessel formation. By designing biomaterials to control stem cell differentiation, this CAREER project seeks to determine the roles of oxygen signaling and environmental cues in regulating lymphatic vessel formation during early development. Ultimately, the proposed research promises to uncover the mechanism underlying lymphatic growth. In addition, the integrated education and outreach programs aim to promote learning at all levels by focusing on early engagement of students in service learning to inspire their interests in STEM fields. This project supports education and broadening participation by: (1) stimulating interests in stem cell research through a science exhibit; (2) introducing middle school students to the emerging field of biomaterials using hands-on modules; and (3) educating high school teachers and students through NSF’s Research Experience for Teachers (RET) on contemporary topics in bioengineering.The investigator’s long-term research goal is to use engineering principles to make breakthroughs in stem cell differentiation and lymphatic vessel morphogenesis, while integrating research with education and training of engineers for the future workforce. Toward this goal, this CAREER project aims to integrate research and education programs dedicated to the transdisciplinary investigation of functional interactions between hypoxia-signaling pathways and matrix-driven cues that are essential for stem cell differentiation into lymphatic endothelial cells (LECs) and eventually their morphogenesis to form lymphatic vasculatures. Specifically, the three fundamental questions to be addressed are: (1) How do changes in oxygen concentrations during the early separation process between the blood and lymphatic networks affect the fate of vascular progenitor cells into LECs? (2) How are matrix types (e.g., hyaluronic acid, collagen) and properties (e.g., stiffness, mesh size, degradation) altered during lymphatic morphogenesis and network assembly in vitro? and (3) What functional interactions occur between hypoxia and matrix-driven cues during lymphatic network assembly? To answer these important questions, the proposed research will utilize a transdisciplinary approach that covers many fields from polymer science to stem cell and lymphatic biology. Collectively, this project will develop fundamental knowledge that can aid in stimulating lymphatic vessel growth, enabling effective and robust cell-based therapies, as well as in vitro models for diseases and drug development.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.