ABSTRACT

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.

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