Collaborative Research: Mechanical Regulation of Cell Death

University Of Massachusetts Medical School, Worcester MA

Investigators

Abstract

For a person to be healthy, cells must be created and, at the right time, sometimes die. There are many diseases that are caused by cells that don't die at the correct time. The death of cells is changed by physical forces applied to and generated within tissues. However, relatively little is known about how the forces change the timing or speed of cell death. The interior molecules of a cell create and carry loads between cells. The goal of this research is to determine the specific role of the molecule actin, and the pathways that control actin, in the mechanical regulation of cell death. The work will identify small and large size molecules that can be manipulated by drugs to change how loads regulate cell death in many diseases, including tumors, heart disease, arthritis and osteoporosis. The project will support training of a doctoral student and six undergraduate researchers (REU) mentored between our campuses. As part of the program, these student researchers mentor girls from underserved middle-schools in a one-week program focused on gaining confidence through independent mini-research projects. This project will advance the fundamental understanding of how forces are generated by single cells and within the context of multicellular tissues. It will elucidate how mechanical forces regulate cell death. The role of cell forces and actin dynamics in apoptosis will be studied at multiple scales; in clusters of cells, in individual cells, and at the molecular signaling scale. The overall approach is mechanics-based and combines experimental and computational models that inform each other to obtain accurate maps of the force distribution within cells and tissues. The work will identify how mechanical forces, the actin cytoskeleton, and relevant signaling pathways collectively regulate apoptosis. Quantitative knowledge of the mechanical signals that induce apoptosis and the mechanisms transmitting these signals is fundamental for understanding the underlying pathophysiology of various disease states that involve improper control of cell death. 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.