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REPROGRAMMING LUNG FIBROBLASTS INTO LUNG PROGENITORS

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abstract
Pulmonary Fibrosis (PF) is characterized by the replacement of functional lung parenchyma with fibrotic tissue. PF develops due to chronic injury to the lungs, and leads to decreased lung compliance, function and a significant reduction in the quality of life for the patient. Currently, there are no treatments available that can reverse fibrosis once it has occurred. Reprogramming technology provides exciting avenues for treatment of disease. Direct reprogramming involves the conversion of one cell type directly into another; fibroblasts have been reprogrammed into neural, cardiac and hepatic lineages using forced expression of lineage-specific transcription factors. This strategy offers the possibility of regenerating damaged tissue in vivo by reprogramming resident cells to stimulate tissue regeneration. If resident fibroblasts within fibrotic tissue could be reprogrammed directly into a lung progenitor phenotype, this could drive the formation of new functional tissue and improve lung function. We hypothesize that reprogramming technology can be used to induce lung fibroblasts into a lung progenitor phenotype in vitro. The goal of this study is to identify reprogramming factors capable of converting fibroblasts into a multipotent lung progenitor phenotype, with the application of this strategy in vivo to ameliorate established pulmonary fibrosis. To identify the transcription factors involved in lung development, we will use ESCs and differentiate them towards lung epithelial cells in vitro in a step-wise manner mimicking early lung development. ESCs will go through a lung progenitor stage before maturing to lung epithelial cells. Transcription factor expression at the lung progenitor stage will lead to identification of lung lineage-specific transcription factors that could possibly reprogram fibroblasts into lung progenitors. Co-expression of multiple transcription factors, each with unique functional roles, will likely be required for direct reprogramming. Hence, we will assess different combinations of lung lineage-specific transcription factors to determine the optimal combination of factors needed for reprogramming in vitro.
subject
differentiation
embryonic stem cells
fibroblasts
lung epithelial cells
lung progenitors
reprogramming
contributor
Kidiyoor, Amritha (author)
Atala, Anthony J (committee chair)
Murphy, Sean V (committee member)
Seeds, Michael (committee member)
Files, Daniel C (committee member)
Soker, Shay (committee member)
Jackson, John (committee member)
date
2018-05-24T08:36:15Z (accessioned)
2018 (issued)
degree
Molecular Medicine and Translational Science (discipline)
2023-05-22 (liftdate)
embargo
2023-05-22 (terms)
identifier
http://hdl.handle.net/10339/90747 (uri)
language
en (iso)
publisher
Wake Forest University
title
REPROGRAMMING LUNG FIBROBLASTS INTO LUNG PROGENITORS
type
Dissertation

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