Doctor of Philosophy (PhD)
Molecular Genetics & Cell Biology
Andrew T. Dudley, PhD
Biological tissues continuously experience mechanical stress and have evolved sophisticated mechanisms to sense mechanical stimuli. While traditional viewpoints regard cells as the ultimate sensors and processors of mechanical information, compounding evidence demonstrates that extracellular matrix, the structural component of tissues, also exhibits evolved molecular responses to force. This led us to propose a new paradigm termed extracellular mechanotransduction, in which matrix orchestrates a complementary form of force integration distinct from traditional cellular and extracellular viewpoints. We thus propose that force-sensitive signaling mechanisms evolved within the extracellular space to help cells maintain mechanical homeostasis in tissues. In this dissertation, we apply this novel perspective to explore new paradigms in health and disease, selecting Marfan syndrome, a heritable connective tissue disorder caused by mutations in the extracellular matrix protein fibrillin-1, as our prototypical example. Using computational molecular dynamics and single-molecule biophysical techniques, we reveal fibrillin-1 calcium-binding is force-sensitive and show that mutations linked to Marfan syndrome perturb this tension-based mechanism. Overall, these studies support extracellular mechanotransduction by reimagining fibrillin-1 as a novel extracellular force-sensor. We concluded by proposing the mechanosensitive properties of fibrillin-1 itself as an innovative next-generation therapeutic target for Marfan syndrome.
Haller, Stephen, "Extracellular Mechanotransduction in Marfan Syndrome: An Equivalence Principle" (2022). Theses & Dissertations. 616.
Available for download on Sunday, February 11, 2024