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Principal Investigator: Sandeep K Agarwal
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $556,482
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <Address><Adhesion Molecule><Architecture><Autoimmune><Behavior><Biology><Bleo><Bleomycin><Body Tissues><Cadherins><Cause of Death><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell surface><Cell-Extracellular Matrix><Cells><Clinical><Clinical Treatment Moab><Complex><Cre Lox technology><Cre LoxP system><Cre lox recombination><Cre lox recombination system><Cre lox system><Cre recombinase/LoxP technology><Cre system><Data><Deposit><Deposition><Dermal><Development><Disease><Disorder><ECM><Engineering><Engineering / Architecture><Epithelial Cells><Exposure to><Expression Signature><Extracellular Matrix><Fibroblasts><Fibrosis><Fibrotic lesions in lung><Gene Expression Profile><Gene Transcription><Genetic Transcription><Heart><In Vitro><Interstitial Lung Diseases><Intestinal><Intestines><Label><Laboratories><Liposomal><Liposomes><Liver Fibrosis><LoxP-flanked allele><Lung><Lung Alveolar Epithelia><Lung Respiratory System><Lung Tissue Fibrosis><Lung scar><Lung tissue scar><Macrophage><Mediator><Mice><Mice Mammals><Modeling><Molecular><Molecular Target><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Mouse Strains><Murine><Mus><Mφ><Nanotechnology><OB-cadherin><Pathogenesis><Pathway interactions><Population><Pulmonary Fibrosis><Pulmonary Scar><Pulmonary Tissue fibrosis><RNA Expression><Regulation><Role><STAT3><STAT3 gene><Scarring at the lung><Scarring in the lung><Scleroderma><System><Systemic Scleroderma><Systemic Sclerosis><Therapeutic><Tissues><Transcription><Transgenic Mice><alveolar epithelium><assess effectiveness><bowel><cadherin-11><cell adhesion protein><cutaneous fibrosis><dermal fibrosis><dermatosclerosis><determine effectiveness><developmental><effectiveness assessment><effectiveness evaluation><evaluate effectiveness><examine effectiveness><fibrogenesis><fibrosis in the lung><fibrotic liver><fibrotic lung><fibrotic skin><floxed><floxed allele><gene expression pattern><gene expression signature><hepatic fibrosis><in vivo><inhibitor><injured><intraperitoneal><lipid based nanoparticle><lipid nanoparticle><liposomal delivery><liposome delivery><lung development><lung fibrosis><mAbs><monoclonal Abs><mortality><mouse model><murine model><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanocarrier><nanoparticle><nanosized particle><nanotech><nanotechnological><nanovessel><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><osteoblast cadherin><pathway><prevent><preventing><progressive systemic sclerosis><pulmonary><recruit><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skin fibrosis><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tool><transcriptional profile><transcriptional signature><transcriptomics><uptake>