The research objective of this award is to elucidate a potential relationship between the mechanical and biochemical properties of the nucleus in a tissue cell to the mechanical microenvironment of different tissues. For example, brain tissue is soft while bone is far stiffer, raising the question as to whether mechanical differences between tissues are reflected in mechanical differences between nuclei in these tissues. A combination of single cell mechanical tools, modern biochemical characterization tools, and statistical mechanics tools will be developed in application to a range of human and mouse tissues thru isolated nuclei. The nucleus confines, protects, and regulates the genome that is common to the roughly 200 different cell types in the adult. The nucleus also possesses an assembly of structural proteins called lamins that are likely to have a key mechanobiological role, but biochemical analyses will extend to a more complete set of nuclear proteins. Cultured cells in which the level of a given component is varied will be studied with fluorescence-coupled micro-aspiration methods to determine the impact on mechanical properties, and stem cell cultures will ultimately provide insight into the impact on differentiation processes. In parallel, nuclear assemblies will be simulated with an increasing level of molecular detail by coarse-grained statistical mechanical methods developed for simple cells such as red blood cells.
These studies could add significantly to the field's understanding of tissue and nuclear mechanics in relation to lineage-dependent gene expression, i.e. differentiation, and they could benefit developmental physics, and regenerative medicine among other fields. The educational plan focuses on development of a course on stem cells and proteomics from a soft matter perspective. Local high school science teachers will assist in nuclear isolations as well as nano- and micro- mechanical characterizations, with the aim of dissemination, while outreach through research experiences for undergraduates will help to encourage students to pursue higher degrees.
