EXPLORING THE ROLE OF NUCLEAR ENVELOPE PROTEINS IN FORCE TRANSMISSION, NUCLEAR MECHANICS, AND MUSCULAR DISEASE

Abstract

Proteins associated with the nucleus’ double lipid membrane system (i.e., nuclear envelope proteins) have gained increasing attention in recent years. The bulk of my dissertation work focuses on the development and application of technologies to quantify the contribution of nuclear envelope proteins to the mechanical wiring within living cells. These powerful assays enable measurements of nuclear deformations, nuclear movements (e.g., during muscle differentiation) and nucleo-cytoskeletal force transmission in response to both intra- and extracellular-generated forces. Diseases caused by mutations in genes encoding nuclear envelope proteins, such as Emery-Dreifuss muscular dystrophy, often have convoluted mechanisms due to the multifaceted role of the nuclear envelope in a variety of biochemical and mechanical cellular processes. Therefore, the assays presented herein are particularly valuable in determining the relative contribution of certain proteins to cellular health and disease when they are absent or mutated. While much of my work supports the idea that that mutations in nuclear envelope proteins cause mechanical defects that render the nucleus less stable and more susceptible to physical damage that results in disease, I have also begun investigating whether nuclear envelope proteins can instantaneously translate mechanical force into transcriptional changes, thus addressing a major question in the field of mechanobiology.