CAREER: Hypoxia and Extracellular Matrix Remodeling in Vascular Differentiation and Network Assembly

职业：血管分化和网络组装中的缺氧和细胞外基质重塑

• 批准号: 1054415
• 负责人: Sharon Gerecht
• 金额: $ 44.98万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1054415&HistoricalAwards=false
• 关键词: CAREER; Hypoxia; Extracellular; Matrix; Remodeling

Gerecht1054415This CAREER project aims to integrate research and education programs dedicated to the interdisciplinary investigation of functional interactions between hypoxic pathways and matrix-driven cues that are essential for vascular morphogenesis and network assembly. The proposed research is based on an interdisciplinary approach to the study and basic understanding of vascular network assembly and requires a particular knowledge set, covering stem cell and vascular biology, as well as engineering fundamentals. The proposed research promises both to uncover the mechanisms underlying vasculature growth and to elucidate the interfaces involved in vascular development signaling pathways for vascular regeneration applications.Early in development and during ischemic disorders, the passive diffusion of oxygen andnutrients becomes limiting; responses to decreased oxygen levels, or hypoxia, are required for the normal development of the vascular system or vascular regeneration. Additionally, the three dimensional cellular environment function as a physical anchor and generates a number of extrinsic factors that control vascular assembly. The differentiation of human embryonic stem cells has been shown to recapitulate aspects of early embryogenesis in sequential stages, hence providing a tool to explore molecular events that take place during human vascular development and, most likely, vascular growth in adulthood. The objectives of the research plan are: (1) to determine vascular progenitor responses to hypoxia; (2) To analyze the network assembly of vascular derivatives in hydrogels; and (3) To examine the hypoxic network assembly of vascular derivatives in hydrogels.The research will be complemented by integrated educational and outreach activities that promote teaching and learning across minority and under-represented groups. For high school and undergraduate students, it could initiate an interest in the fields of stem cell engineering and regenerative medicine through hands-on and laboratory learning. It will expose international students to fields in which they currently receive no education. Finally, as engineering is not introduced in many public school curriculums until high school, the Science, Technology, Engineering and Math (STEM) mentorship program will expose inner city school students to activities they otherwise might not experience and may spark their interest in science while providing them with opportunities for academic success.

Gerecht 1054415这个职业项目旨在整合研究和教育计划，致力于缺氧通路和基质驱动的线索之间的功能相互作用的跨学科研究，这些线索对血管形态发生和网络组装至关重要。拟议的研究是基于跨学科的方法来研究和血管网络组装的基本理解，并需要一个特定的知识集，涵盖干细胞和血管生物学，以及工程基础。这项研究有望揭示血管生长的潜在机制，并阐明血管发育信号通路中涉及的界面，用于血管再生应用。在发育早期和缺血性疾病期间，氧气和营养物质的被动扩散变得有限;对氧气水平降低或缺氧的反应是血管系统正常发育或血管再生所必需的。另外，三维细胞环境起到物理锚的作用，并产生许多控制血管组装的外在因素。人类胚胎干细胞的分化已被证明在连续阶段重演早期胚胎发生的各个方面，因此提供了一种工具来探索人类血管发育期间发生的分子事件，并且最有可能是成年期的血管生长。研究计划的目标是：（1）确定血管祖细胞对缺氧的反应;（2）分析血管衍生物在水凝胶中的网络组装;（3）检查血管衍生物在水凝胶中的缺氧网络组装。该研究将通过综合教育和推广活动进行补充，促进少数民族和代表性不足的群体的教学和学习。对于高中和本科生，它可以通过动手和实验室学习引发对干细胞工程和再生医学领域的兴趣。它将使国际学生接触到他们目前没有接受教育的领域。最后，由于工程学直到高中才在许多公立学校的课程中引入，科学，技术，工程和数学（STEM）导师计划将使内城学校的学生接触到他们可能不会经历的活动，并可能激发他们对科学的兴趣，同时为他们提供学术成功的机会。