This proposal studies the mechanism of cell nucleus rupture and repair in vivo. Animal cells contain specialized structures, called organelles, which are bounded by a membrane and perform specific functions critical for cell survival. The most prominent organelle in animal cells is the nucleus that houses the cell's genetic material and protects it from damage. Exciting observations in the past few years of metastatic cancer cells and immune cells migrating in vitro have shown that cell nuclei can rupture and be damaged severely, however surprisingly cells can repair the nucleus and the cell can continue to live. With this award, the PI will study inside how, a living organism, the nucleus performs its protective function. This research focuses on how nuclei stay intact when forces within cells and tissues are imposed on them. This work will reveal the basic principles of how the nucleus encases and protects the cell's genetic material, which is essential to cell and organismal survival. During the project period, an interactive hands-on workshop that is part of the Yale Pathways to Science Program will provide local high school students an authentic research experience enabling them to see the purpose of using model organisms in science discovery and solving societal problems. The goal of the workshop is to provide URM and female students that have traditionally had their thoughts underrepresented in the sciences a lens into the daily life and excitement of a scientist and, ultimately, help them gain confidence and motivation to persist in the sciences. The workshop curriculum will be refined and made available online in a web-based format to be used as a resource by other universities.
The nuclear envelope forms a physical barrier that serves to regulate and protect the genome. In contrast to the textbook description of the nuclear envelope as a static barrier between the nucleoplasm and cytoplasm, the nuclear envelope is highly dynamic and undergoes local membrane remodeling such as membrane budding, fusion, rupture and repair, as well as global membrane remodeling in open mitosis. Transient nuclear ruptures are a type of local remodeling in which a region of the nuclear envelope ruptures and is subsequently resealed to restore genome compartmentalization. Little is known about how the nuclear envelope prevents ruptures, and promotes repair of ruptures to ensure genome protection, especially in vivo. The objective of this research project is to define the underlying principles of nuclear rupture and repair in a living, intact organism. The research will use the model organism Caenorhabditis elegans, a simple, transparent nematode that undergoes invariant development allowing for quantitative analysis of nuclear envelope dynamics during cellular and tissue morphogenesis. The research project will also employ a combination of innovative laser cutting tools, mathematical predictions, and RNAi-mediated perturbations. The findings are likely to be of broad importance to understanding nuclear envelope dynamics and genome protection in diverse cellular processes and behaviors.
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.
