CAREER: Decoding the Developmental Extracellular Niche for Instructing Lung Tissue Engineering

职业：解码发育细胞外生态位以指导肺组织工程

• 批准号: 2145181
• 负责人: Xi Ren
• 金额: $ 55万
• 依托单位: Carnegie-Mellon University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2145181&HistoricalAwards=false
• 关键词: CAREER; Decoding; Developmental; Extracellular; Niche

How we engineer human tissues is usually inspired by how these tissues are induced in the body during embryonic development and how they regenerate following an injury. The objective of this CAREER project is to uncover the dynamic changes in the extracellular biomolecular environment that support lung tissue maturation during development and during surgical resection induced regeneration. This information will then be used to guide the engineering of novel extracellular biomaterials to enable directed lung tissue maturation in the laboratory setting from human induced pluripotent stem cells (hiPSCs). By identifying and validating the essential extracellular factors, this project will lay the foundation for deriving functional human lung tissues to help patients suffering from end-stage lung diseases and will inspire novel therapeutics promoting lung repair and regeneration following injuries. The research efforts of the CAREER project are integrated with educational and outreach objectives to promote active learning and automated student behavior analysis in the biomedical engineering classroom, to develop an outreach program to encourage and inspire local high school students by hosting educational poster sessions, and to promote biomedical engineering research and education towards the general public through collaboration with a local museum focusing on biological arts.The investigator's long-term research goal is to engineer lung tissues that meet unique physiological and functional requirements. Towards this goal, the objective of this CAREER project is to catalog the dynamic synthesis and secretion of extracellular matrix (ECM) glycoproteins over native lung alveologenesis and use this information to instruct the induction of alveolar cells and tissues from hiPSCs. Emerging evidence suggests that the developmentally regulated ECM deposition is pivotal to the maturation of alveolar cells and proper lung tissue morphogenesis. However, a comprehensive survey of de novo ECM synthesis throughout lung development and regeneration has been challenging to obtain, due to the limited sensitivity in detecting the production of new ECM proteins. To address this bottleneck, this research will develop and implement a novel newly synthesized ECM (newsECM) profiling approach for uncovering the dynamic ECM synthetic programs accompanying alveologenesis. This strategy, by selective labeling and enrichment of newsECM proteins free from the bulk pre-existing ECM, will enable ultrasensitive identification of new ECM synthesis with unprecedented daily temporal resolution. This addresses the critical limitation of current ECM proteomics and is well suited for studying highly dynamic processes such as alveologenesis. Building on this technological innovation, this CAREER project will (1) decode the dynamic ECM production during native lung alveologenesis (neonatal and adult post-pneumonectomy), and (2) engineer hiPSC-derived alveologenesis using developmentally inspired ECM scaffolds. Achieving directed alveolar specification from hiPSCs will provide fundamental insights regarding lung development and facilitate the generation of patient-specific lung tissues for drug discovery and regenerative medicine.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.

通常，我们如何设计人类组织的启发是受胚胎发育过程中如何在体内诱导这些组织以及它们在受伤后再生的启发。该职业项目的目的是揭示细胞外生物分子环境的动态变化，这些变化在发育过程中和手术切除过程中支持肺组织成熟。然后，该信息将用于指导新型细胞外生物材料的工程，以从人类诱导的多能干细胞（HIPSC）中实现实验室环境中的定向肺组织成熟。通过识别和验证基本的细胞外因素，该项目将为导致功能性人体肺组织提供基础，以帮助患有末期肺部疾病的患者，并会激发新的治疗剂，从而促进受伤后的肺修复和再生。职业项目的研究工作与教育和宣传目标融为一体，以在生物医学工程课堂中促进积极学习和自动化的学生行为分析，以开发一项宣传计划，以鼓励和激发当地的高中生，通过举办教育海报会议，并促进生物医学工程和教育，以与当地的研究员进行研究，以促进生物医学工程研究和教育，通过与当地的研究员的共同研究，该研究人员与当地的研究员共同研究，以使其与当地的研究员共同进行研究，以便与博物馆的研究人员合作。生理和功能要求。 为了实现这一目标，该职业项目的目的是对本天然肺肺单抗性的动态合成和分泌的动态合成和分泌，并使用此信息来指导HIPSC的肺泡细胞和组织。新兴的证据表明，发育调控的ECM沉积对于肺泡细胞的成熟和适当的肺组织形态发生至关重要。但是，由于检测新的ECM蛋白质的生产有限的敏感性，对整个肺发育和再生进行了对从头开发和再生的全面调查一直在挑战。为了解决这一瓶颈，这项研究将开发和实施一种新型新合成的ECM（NewsECM）分析方法，用于揭示伴随肺泡术的动态ECM合成程序。通过选择性标记和富集NewsECM蛋白质不存在批量前ECM的选择性标记和富集，该策略将可以通过前所未有的每日时间分辨率对新的ECM合成的超敏感鉴定。这解决了当前ECM蛋白质组学的关键局限性，非常适合研究诸如肺泡术等高度动态过程。在这项技术创新的基础上，该职业项目将（1）解码在本地肺肺泡术（新生儿和成人后神经切除术）期间的动态ECM产生，以及（2）使用发育启发的ECM启发的ECM支架。实现HIPSC的定向肺泡规格将提供有关肺发育的基本见解，并促进患者特异性肺组织进行药物发现和再生医学的产生。该奖项反映了NSF的法定任务，并通过评估该基金会的知识功能和广泛的影响来评估NSF的法定任务。