Sunday, April 28, 2024
4/28/2024
Project Summary/Abstract. Scleroderma (systemic sclerosis, SSc) is a progressive multisystem, autoimmune fibrotic disease with a high morbidity and mortality. SSc associated interstitial lung disease is a leading cause of death. Despite important advances in our understanding of SSc, treatment options remain limited. Identifying novel therapeutic targets for SSc is a major unmet need. Fibrosis, the cardinal manifestation of SSc, is the excessive extracellular matrix deposition, that damages the normal lung architecture and compromises the function of tissues. Our laboratory has identified cadherin-11 (Cdh11) as a novel regulator skin and lung fibrosis. How Cdh11 regulates fibrosis is not completely understood and the current proposal will add to our understanding of the mechanism by which Cdh11 regulates fibrosis as well as apply our understanding of Cdh11 in fibrosis to identify new fibrosis targets and Cdh11 targeted therapeutics The current proposal will prove the hypothesis that cadherin-11 regulates the development of lung fibrosis through modulation of macrophage, alveolar epithelial cell and fibroblast behavior. We also hypothesize that understanding Cdh11 regulation of fibrosis can help identify new regulators of fibrosis such as MafB and that Cdh11 can be used to target nanocarriers in the treatment of fibrosis. Proposed herein are three independent aims. Aim 1 will further our understanding by using our unique Cdh11 transgenic mice that will enable cell specific deletion of Cdh11 on macrophages, type II alveolar epithelial cells and fibroblast. Lung fibrosis will be investigated in these mice and transcriptomic approaches will help understand the mechaniss that Cdh11 regulates fibrosis. Aim 2 use transcriptomic approaches to identify new Cdh11 dependent pathways involved in the development of lung fibrosis and will determine the extent to which MafB, a Cdh11 dependent transcriptional footprint in lung fibrosis, contributes to the development of lung fibrosis. Aim 3 will develop novel anti-Cdh11 monoclonal antibody containing liposomes to deliver STAT3 inhibitors to Cdh11 expressing cells to prevent and treat fibrosis. These studies will take advantage of unique tools such as our unique mouse strains and anti-Cdh11 mAb liposomes along with our team's expertise in cadherins, macrophage biology, fibrosis, transcriptomics and nanotechnology to accomplish these aims. AIM 1. To elucidate the requirement of cadherin-11 in macrophages, type II alveolar epithelial cells and fibroblasts in the orchestration of macrophage recruitment and lung fibrosis. AIM 2. To investigate the extent to which MafB regulates fibrosis in vitro and in vivo and use transcriptomic approaches to identify additional novel cadherin-11 regulated pathways that regulate fibrosis. AIM 3. To develop cadherin-11 targeting liposomes and determine the extent to which cadherin-11 can serve as a molecular target for liposomal delivery of fibrosis therapeutics.
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