Professor Dahl's research uses rheological, biophysical and optical techniques to understand the structure and organization of the cell nucleus. These studies are relevant to dissecting the molecular pathology of diseases caused by defects in nuclear structure.
Diseases of the nuclear lamina
Many diseases result from the loss or mutation of lamins and other structural proteins at the nuclear envelope and in the nuclear interior. Diseases include Hutchinson-Gilford Progeria Syndrome (premature aging), Emery-Dreifuss Muscular Dystrophy and Dilated Cardiomyopathy. Nuclear mechanical integrity is significantly altered in some cells of these patients. Professor Dahl's studies compare normal cells with cells in which structural proteins are either chronically absent (as in knockout animals or disease patient cells) or rapidly down-regulated (as by RNAi-mediated gene silencing). These studies reveal the adaptations made by nuclei to altered mechano-structural environments in order to restore function.
Stem cell differentiation and cancer progression
Nuclear shape and chromosome positioning change dramatically during stem cell differentiation and cancer progression. However, these changes have not been quantified and their downstream effects are poorly understood. Fluorescence techniques are being combined with quantitative biophysics to track recruitment of transcription factors or cell cycle regulators to differentiationspecific or cancer-specific genes while cells or nuclei are under well-defined imposed forces.
Mechanotransduction
Mechanotransduction allows cells to sense mechanical forces and adapt by changing gene expression. Signal transduction to the nucleus plays a significant role in gene expression, but mechanical forces may also propagate through the cell to the nucleus. Combining molecular biology and mechanical measurements with computational continuum mechanical modeling allows determination of the range of forces that can be transduced into the nucleus. Simultaneously, molecular force-induced changes in gene expression can be examined for any system of interest. These studies are central to tissue and cellular engineering to provide cells in an artificial environment with the correct mechanical information.
