BRITE Fellow: The Mechanobiology of Sex and Stress

BRITE 研究员：性与压力的机械生物学

• 批准号: 2227509
• 负责人: Beth Pruitt
• 金额: $ 100万
• 依托单位: University of California-Santa Barbara
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2227509&HistoricalAwards=false
• 关键词: BRITE; Fellow; Mechanobiology; Sex; Stress

This Boosting Research Ideas for Transformative and Equitable Advances in Engineering (BRITE) Fellow award is to advance the Nation's understanding of the ways that male and female heart muscle cells handle stress differently. Recent studies have revealed significant differences in male and female biology, including disease progression and responses to stress in the heart. Importantly, these differences are observed not only in whole organs, but at the cellular level as well. The heart is the most mechanically stressed organ in our body. Specialized heart muscle cells serve as the motor units driving each heartbeat to pump blood throughout our bodies. While it is known that the hearts of mice, men and women vary in important details like size, heart rate, and protein composition, the fundamental mechanisms that cause these differences are not yet identified. There is a lack in access to human heart cells for comprehensive studies, mostly because these cells do not renew after biopsy, injury or disease. In this project, new sources of human heart cells that represent the diversity of society are developed and validated and their responses to stressors are studied by involving engineering, biology, statistics, and computer science. This multidisciplinary approach will support diverse workforce development and create education and training opportunities for undergraduate and graduate students who will become the next generation of researchers and science leaders. This project will highlight the importance of diversity in the basic science and fundamental understanding of physiological responses by disseminating data, models and best practices through publication and outreach at scientific meetings and events in the community.Currently, a lack of models, human cell lines, and the methods to link cellular sex and mechanobiological stress responses exists. This project aims to develop and validate protocols for generating human heart muscle cells from induced stem cell lines obtained from a diversity of adult donors. To learn how and why male and female cells handle stress differently at the cellular level, these cells will be stressed with mechanical and chemical means and observed as to how they respond and change their structure and function, and further how they regulate key signaling proteins linked to physiological stress. This research will provide new insights into the interplay of differentially regulated sex genes and the integrated stress response. It will also cultivate new insights into muscle mechanobiology and how stress and sex cooperate to mediate cell maintenance and energy expenditures to facilitate contractile function and cellular remodeling under stress. This project will generate the aligned multi-modal data (images, videos, sequences), experimental meta-data, and sufficiently aligned and annotated data sets across a range of male and female stem cell lines that will be ultimately suitable for machine learning approaches by the research community. These data will be shared through publicly available repositories such as GEO, UC library archives, and the BisQue (Bio-Image Semantic Query User Environment) platform hosted at UCSB. The research outcomes and data will benefit researchers working on the development of cell and tissue engineering models and their application to preclinical biomedical inquiry. In the longer term, communities and groups that are under-represented in current studies (women, racial minorities) will benefit from the inclusion of representative cellular data.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.

这个促进工程学中变革性和公平进步的研究想法(BRITE)院士奖是为了促进全国对男性和女性心肌细胞处理压力的不同方式的理解。最近的研究表明，男性和女性在生物学上存在显著差异，包括疾病进展和心脏对压力的反应。重要的是，这些差异不仅在整个器官中观察到，而且在细胞水平上也观察到。心脏是我们身体中机械压力最大的器官。专门的心肌细胞是驱动每一次心跳的马达单位，将血液输送到我们的全身。虽然众所周知，老鼠、男人和女人的心脏在大小、心率和蛋白质组成等重要细节上存在差异，但导致这些差异的基本机制尚未确定。缺乏获取人类心脏细胞进行全面研究的机会，主要是因为这些细胞在活组织检查、损伤或疾病后不会更新。在这个项目中，开发和验证了代表社会多样性的新的人类心脏细胞来源，并通过工程学、生物学、统计学和计算机科学来研究它们对应激源的反应。这种多学科的方法将支持多样化的劳动力发展，并为本科生和研究生创造教育和培训机会，他们将成为下一代研究人员和科学领导者。这个项目将通过在社区的科学会议和活动中发表和推广数据、模型和最佳实践来强调基础科学和生理反应基础理解的多样性的重要性。目前，存在着缺乏将细胞性别和机械生物应激反应联系起来的模型、人类细胞系和方法。该项目旨在开发和验证从不同成人捐赠者获得的诱导干细胞系生成人类心肌细胞的方案。为了了解雄性和雌性细胞如何以及为什么在细胞水平上处理不同的压力，这些细胞将受到机械和化学手段的压力，并观察它们如何响应和改变其结构和功能，以及它们如何调节与生理应激有关的关键信号蛋白。这项研究将为不同调控的性基因和综合应激反应之间的相互作用提供新的见解。它还将培养对肌肉机械生物学的新见解，以及压力和性别如何协同调节细胞维护和能量支出，以促进应激下的收缩功能和细胞重塑。该项目将生成经过比对的多模式数据(图像、视频、序列)、实验元数据以及经过充分比对和注释的一系列雄性和雌性干细胞系的数据集，这些数据集最终将适用于研究界的机器学习方法。这些数据将通过公共可用的储存库共享，如GEO、UC图书馆档案和设在UCSB的BISQUE(生物图像语义查询用户环境)平台。研究成果和数据将有利于致力于细胞和组织工程模型开发及其在临床前生物医学研究中的应用的研究人员。从长远来看，在当前研究中代表性不足的社区和群体(妇女、少数族裔)将受益于纳入具有代表性的蜂窝数据。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。