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Principal Investigator: Lindsey A Miles
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2024
Award: $460,000
Funding agency: National Heart Lung and Blood Institute
Project Summary/Abstract
The plasminogen activation system extensively regulates the inflammatory response in a broad range of
tissues. Inflammation is essential for maintenance of normal tissue homeostasis and its dysregulation has a
broad pathologic impact, including development of fibrosis, scarring, aberrant wound healing, infection, sepsis,
autoimmune disease and asthma. A critical gap in knowledge is understanding the mechanisms by which
plasminogen communicates with cells to regulate inflammatory responses. Plg-RKT is a novel integral membrane
protein that binds plasminogen via a C-terminal lysine exposed on the cell surface and promotes cell surface
plasminogen activation. The long-term goal of our laboratory is to understand mechanisms by which Plg-RKT
regulates physiologic and pathologic processes. This proposal is based on new data showing that Plg-RKT
promotes expression of CCL2, a key mediator of the pro-inflammatory response, and a potential intervention
point for the treatment of diseases with an inflammatory component. Additional results support the provocative
concept that regulation of CCL2 expression, rather than cell surface proteolysis of extracellular matrix, appears
to be the primary mechanism for plasminogen/Plg-RKT control of mononuclear cell recruitment in the
inflammatory response in vivo. The central hypothesis to be addressed is that plasmin(ogen)/Plg-RKT-
dependent promotion of CCL2 expression is the primary mechanism for promotion of plasmin(ogen)/Plg-RKT-
dependent mononuclear cell recruitment in the inflammatory response. The hypothesis will be tested in murine
models of pleurisy and peritonitis. And we will investigate the role of Plg-RKT in the inflammatory response in
asthma because in T helper type 2 (Th2) immune-related diseases, such as asthma, CCL2 is expressed at high
levels and its neutralization in animal models ameliorates disease. The objectives of this proposal are to
investigate the role of Plg-RKT in CCL2 synthesis in vivo and assess its impact on Plg-RKT-dependent
mononuclear cell recruitment and to examine the role of Plg-RKT in the pathogenesis of asthma. Our specific
aims are (1) to investigate the role of Plg-RKT in CCL2 synthesis in vivo and its impact on Plg-RKT-dependent
mononuclear cell recruitment and (2) to examine the role of Plg-RKT in the pathogenesis of asthma. We will use
Plg-RKT deficient mice and mice over-expressing Plg-RKT to test whether plasmino(ogen)/Plg-RKT-dependent
CCL2 up-regulation in vivo is PAR-1- dependent. We will use single cell RNA sequencing to identify cell types
responsible for Plg-RKT-dependent stimulation of CCL2 expression and we will determine whether exogenously
added CCL2 can rescue the impairment in macrophage recruitment in Plg-RKT-/- mice. We will investigate the
role of Plg-RKT in inflammation in ovalbumin-induced asthma and determine whether Plg-RKT regulates airway
hyper-responsiveness (AHR). We expect that accomplishment of our specific aims will establish Plg-RKT as a
pivotal regulator of the inflammatory response via regulation of expression of the key chemoattractant, CCL2,
and provide fundamental insights into how mononuclear cell recruitment is regulated.
Terms: <21+ years old><Address><Adult><Adult Human><Airway Hyper-responsiveness><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Apoptotic><Asthma><Autoimmune Diseases><Autoregulation><Binding Proteins><Blood Coagulation Disorders><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><Body Tissues><Bronchial Asthma><C-terminal><CCL2><CCL2 gene><COVID-19><CV-19><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell surface><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Regulation><Cessation of life><Chemoattractants><Chemokine, CC Motif, Ligand 2><Chemotactic Factors><Chemotaxins><Cicatrix><CoV emergence><Coagulation Disorder><Coagulopathy><Communication><Coronaviridae Infections><Coronavirus Infections><Coronavirus Infectious Disease 2019><Data><Death><Development><Disease><Disorder><EC 3.4.21.7><ECM><Extracellular Matrix><Fibrinolysin><Fibrosis><Funding><Glu-Plasmin><Goals><Heart Vascular><Homeostasis><Hospital Admission><Hospitalization><Immune><Immunes><Impairment><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Integral Membrane Protein><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intrinsic Membrane Protein><Investigation><Knowledge><L-Lysine><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Lung><Lung Respiratory System><Lysine><MCAF><MCP-1><MCP1><Macrophage><Maintenance><Marrow Neutrophil><Marrow monocyte><Mediator><Mice><Mice Mammals><Modeling><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Mononuclear><Murine><Mus><Mφ><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Normal Tissue><Normal tissue morphology><Organism-Level Process><Organismal Process><Ovalbumin><Pathogenesis><Pathologic><Pathologic Processes><Pathological Processes><Patients><Peritonitis><Phagocytosis><Phenotype><Physiologic Processes><Physiological Homeostasis><Physiological Processes><Plasmin><Plasminogen><Play><Pleurisy><Pleuritis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Profibrinolysin><Protease F><Protein Binding><Protein Cleavage><Proteolysis><Proteomics><Public Health><Regulation><Research><Resolution><Role><SCYA2><Scars><Sepsis><Severity of illness><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Inducible Cytokine A2><Subcellular Process><Syndrome><System><Testing><Tissues><Transmembrane Protein><Transmembrane Protein Gene><Up-Regulation><Upregulation><Wound Repair><adulthood><airway hyper-reactivity><airway hyperactivity><airway hyperreactivity><airway hyperresponsiveness><airway hypersensitivity><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><bleeding disorder><blood infection><bloodstream infection><bound protein><cell growth regulation><cell type><circulatory system><clotting disorder><co-morbid><co-morbidity><comorbidity><complement chemotactic factor><corona virus emergence><coronavirus disease 2019><coronavirus disease-19><coronavirus emergence><coronavirus infectious disease-19><developmental><disease severity><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><in vivo><inflammatory mediator><insight><interventional strategy><model of animal><monocyte><mouse model><murine model><nCoV><neutrophil><new CoV><new corona virus><new coronavirus><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel CoV><novel corona virus><novel coronavirus><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><plasminogen receptor><pulmonary><recruit><resolutions><respiratory><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><wound healing><wound recovery><wound resolution>