Mutations in the gene encoding surfactant protein A2 (SP-A2) cause familial idiopathic pulmonary fibrosis (IPF) and lung cancer, both lethal diseases with limited treatment options. The molecular mechanism of mutant surfactant proteins are not well understood and underlie a spectrum of lung diseases affecting children and adults. We have recently discovered that expression of certain mutant surfactant proteins in lung epithelial cells leads to increased expression and secretion of latent TGF-, a potent pro-fibrotic and pro-oncogenic cytokine. The specific hypothesis to be tested is that expression of mutant surfactant proteins in alveolar epithelial cells leads to pulmonary fibrosis through the autocrine and paracrine effects of TGF-, whose secretion is induced through ER stress-dependent and ER stress-independent pathways. Our rationale for the proposed work is that it will provide enhanced understanding of the gain-of-function effects of mutant surfactant proteins in causing progressive pulmonary fibrosis.
The first aim will focus on studying this mechanism in vitro by determining: Which variant surfactant proteins have a gain-of-function effect of inducing increased latent TGF- secretion and what is the relative contribution of ER stress signaling that mediates this mechanism? The molecular mechanism of the underlying pathways will be probed using a combination of proteomic and transcriptomic approaches as well as chemical inhibitors.
The second aim will define the injury or "reprogramming" of type II alveolar epithelial cells caused by acute or chronic expression of mutant surfactant proteins and the involvement of various pathways that affect the cellular context of TGF- signaling. In the third and last aim, we will elucidate the in vivo molecular mechanism of mutant SP-A2 protein-mediated disease using a novel transgenic mouse model. We will specifically explore the genetic contributions of the TGF- signaling and telomerase pathways in contributing to bleomycin-induced lung fibrosis. While the signaling pathways downstream of TGF- are well characterized, the inciting events that lead to its expression and secretion are not. Successful completion of these aims will elucidate this novel pathway of mutant surfactant induced latent TGF- secretion. This work will generate insight into the pathways linking protein misfolding, ER stress, EMT, cellular differentiation and proliferation in lung fibrosis and will assist in the identification of unique targets for drug development.

Public Health Relevance

The role of TGF- in lung fibrosis has become increasingly evident. At a basic level, understanding the specific signaling events that trigger secretion of TGF- is a key issue that will be addressed in this project using biochemical, cell biology and genetic approaches. These studies will provide insight into the mechanisms by which mutant lung proteins lead to fibrosis and will facilitate development of new therapeutic approaches for this lethal disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121267-01
Application #
8613014
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$462,244
Indirect Cost
$166,949
Name
University of Texas Sw Medical Center Dallas
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390