Dwight had an important influence on the lab through his tremendous imagination and depth of knowledge. He was awarded an elusive F30 MD/PhD Fellowship from the National Heart, Lung and Blood Institute. A tremendous achievement considering that they fund only a few each year. Now he is back in medical school for his final 2 years before launching an academic research career.
A System of Mechanical Genetics with Applications to Pulmonary Fibrosis
Pulmonary fibrosis is a deadly, progressive sclerosis of the lung parenchyma. This
pathology is driven in part from mechanical cues, derived from the extracellular matrix
(ECM), to resident fibroblast populations in the lung. A deeper understanding of this
pathologic mechanotransduction is critical to the development of novel therapeutic avenues
that address matrix-driven fibrosis. This thesis considers how mechanical information is
transduced into genetic decisions by fibroblasts and also explores the potential for nucleic
acids to interfere or hijack this aberrant mechanical signaling. This work is conceptually
organized around the flow of mechanical information from the ECM, through the
mechanically sensitize protein machinery of the cell, ultimately towards the genome of the
cell itself. In Chapter 1 of this work, an introduction to the clinical background of
pulmonary fibrosis is presented. In Chapter 2, the use and in vivo delivery of mRNA to
modulate mechanotransduction at the fibroblast-ECM interface is discussed. In Chapter 3,
the mechanotransductive mechanism of rigidity-driven sensitization of fibroblasts to
transforming growth factor β is explored through the biology of LEM containing protein
3, LEMD3. In Chapter 4, the structure of the murine CArGome, a mechanically regulated
genetic element, is presented. Additionally, the characterization of genetic tools to
understand the thermodynamic landscape of the CArGome is discussed. In Chapter 5,
promising intersections between the ideas and findings of each chapter are put forth as the
basis for potential future work in this area.
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