Date: August 25th, 2015

Time: 1PM

Room: EBB 1005

Committee:

Thomas Barker, PhD (Advisor)

Johnna Temenoff, PhD, GT-BME

Melissa Kemp, PhD, GT-BME

Phil Santangelo, PhD, GT-BME

Lonnie Shea, PhD, U.Mich-BME

A System of Mechanical Genetics through MRTF/SRF Titration with Applications to Pulmonary Fibrosis

Abstract:

The extracellular matrix in pulmonary fibrosis (PF) is the driver of patient morbidity/mortality.  Moreover, the matrix is both the consequence of cellular pathology and a cause of the pathology itself through mechanotransduction.  Remediating the fibrotic matrix directly is not currently possible and, there are few matrix focused therapies in development.  Traditional targeting of the diseased matrix is difficult due to the biochemical similarity between pathologic collagen in fibrosis and collagen in physiological contexts; however, the fibrotic matrix is significantly stiffer than its physiological counterpart.  This proposal seeks to exploit this biophysical characteristic of the fibrotic matrix by characterizing and hijacking a mechanotransductory transcription factor (TF) pathway, the myocardin-related transcription factor-serum response factor (MRTF-SRF) axis.  Specifically, this proposal aims to develop and validate a statistical mechanics model of MRTF-SRF activity in fibroblasts to predict the mechano-sensitivity of transgenes using a high-throughput DNA-TF binding assay, TF localization assays, and a TF luciferase array.  This proposal will also characterize the ability of “decoy” DNA elements to preferentially buffer pathologic signaling in the MRTF-SRF axis.  Success in this project should permit the rational design of mechano-sensitive promoters, more fully characterize an important TF axis, and develop a new gene-based therapeutic for PF.