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.

这一提高了工程学发展和公平进步（BRITE）奖的研究思想是促进国家对男性和女性心肌细胞对压力的应对方式的理解。最近的研究揭示了男性和女性生物学的显着差异，包括疾病进展和对心脏压力的反应。重要的是，这些差异不仅在整个器官中，而且在细胞水平上都观察到。心脏是我们体内最压力的器官。专门的心肌细胞用作运动单位，驱动每个心跳，以在我们体内泵入血液。尽管众所周知，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有所不同，但尚未确定引起这些差异的基本机制。缺乏进入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检，损伤或疾病后不会续签。在这个项目中，发展和验证了代表社会多样性的人类心脏细胞的新来源，并通过涉及工程，生物学，统计和计算机科学来研究其对压力源的反应。这种多学科的方法将支持多样化的劳动力发展，并为将成为下一代研究人员和科学领导者的本科和研究生创造教育和培训机会。该项目将通过在社区中的科学会议和事件上发表和宣传来传播数据，模型和最佳实践在基础科学中的重要性以及对生理反应的基本理解。当然，缺乏模型，人类细胞系以及链接细胞性行为和机械性压力反应的方法存在。该项目旨在开发和验证从多种成年捐助者获得的诱导的干细胞系中产生人心肌细胞的方案。为了了解男性和女性细胞在细胞水平上的应激方式以及为什么的方式，这些细胞将用机械和化学方法强调，并观察到它们如何反应和改变其结构和功能，并进一步调节与生理胁迫相关的关键信号蛋白。这项研究将为差异调节性基因的相互作用和综合应力反应提供新的见解。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介导细胞维持和能量消耗，以促进收缩功能和压力下的细胞重塑。该项目将生成对齐的多模式数据（图像，视频，序列），实验性元数据，并在一系列男性和女性干细胞系中充分排列和注释的数据集，这些数据集最终适用于研究社区的机器学习方法。这些数据将通过公开可用的存储库，例如GEO，UC库档案馆和UCSB托管的Bisque（Bio-Image语义查询用户环境）平台。研究结果和数据将使研究细胞和组织工程模型开发的研究人员及其在临床前生物医学探究中的应用。从长远来看，在当前研究（妇女，种族少数群体）中代表性不足的社区和群体将受益于代表性的蜂窝数据。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子优点和更广泛影响的审查标准通过评估来进行评估的。