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.

这项促进工程变革和公平进步的研究理念 (BRITE) 研究员奖旨在促进国家对男性和女性心肌细胞处理压力的不同方式的理解。最近的研究揭示了男性和女性生物学上的显着差异，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。心脏是我们体内承受机械压力最大的器官。专门的心肌细胞充当运动单位，驱动每次心跳，将血液泵送到我们的全身。虽然众所周知，小鼠、男性和女性的心脏在大小、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。缺乏对人类心脏细胞进行综合研究的机会，主要是因为这些细胞在活检、损伤或疾病后不会更新。在该项目中，开发和验证了代表社会多样性的人类心脏细胞的新来源，并通过工程学、生物学、统计学和计算机科学来研究它们对压力源的反应。这种多学科方法将支持多元化的劳动力发展，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。该项目将通过在社区科学会议和活动中发表和推广来传播数据、模型和最佳实践，强调基础科学多样性的重要性和对生理反应的基本理解。目前，缺乏模型、人类细胞系、并且存在将细胞性别和机械生物学应激反应联系起来的方法。该项目旨在开发和验证从多种成年捐赠者获得的诱导干细胞系中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何在细胞水平上以不同方式处理压力，将通过机械和化学手段对这些细胞施加压力，并观察它们如何反应和改变其结构和功能，以及它们如何调节相关的关键信号蛋白到生理压力。这项研究将为差异调节性基因的相互作用和综合应激反应提供新的见解。它还将培养对肌肉力学生物学以及压力和性如何合作介导细胞维持和能量消耗以促进压力下的收缩功能和细胞重塑的新见解。该项目将生成一系列男性和女性干细胞系中对齐的多模态数据（图像、视频、序列）、实验元数据以及充分对齐和注释的数据集，这些数据集最终将适用于机器学习方法研究界。这些数据将通过公共存储库共享，例如 GEO、加州大学图书馆档案馆和加州大学圣巴巴拉分校托管的 BisQue（生物图像语义查询用户环境）平台。研究成果和数​​据将使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受益。从长远来看，当前研究中代表性不足的社区和群体（女性、少数族裔）将受益于代表性细胞数据的纳入。该奖项反映了 NSF 的法定使命，并通过使用基金会的评估进行评估，被认为值得支持。智力价值和更广泛的影响审查标准。