The Pre-Clinical Models of Acute Lung Injury Core (Core C) is designed to provide PPG investigators with rigorously defined and reproducible murine models of acute respiratory distress syndrome (ARDS) and ventilation-induced lung injury (VILI). The Core will advance three principal objectives with the first objective to provide a complete range of expertise, training, equipment, and data analysis tools to extensively study and characterize the role of cytoskeleton in preclinical models of murine lung injury. We will employ the state-of- the-art techniques to a) characterize the role of cytoskeleton in regulating lung endothelial cell barrier function, b) determine the effects of specific interventions in order to provide insight into the efficacy and mechanisms of novel therapeutic strategies, and c) facilitate the translation of basic research to clinical interventions. Toward this ultimate aim, the Core will first provide validated quantitative measurements of vascular permeability and inflammation. The second objective is to house and care for the genetically-engineered mice utilized in this PPG and to generate novel transgenic and knockout mice (e.g., inducible endothelium conditional knockout mice). The third objective is to examine selective siRNAs or pharmacological agonists or antagonists for cytoskeletal proteins as potential therapeutic strategies and approaches for ARDS and VILI models. The fourth objective will be to provide rigorously performed, protocol-driven performance of specific experimental strategies involving LPS and VILI preclinical models of ARDS/VILI as well as S1P and HGF rescue interventions. The last objective will be to evaluate the function of ARDS-associated SNPs and sites of functional protein post-translational modification (PTM), utilizing mutated cDNA (high efficiency expression plasmids) targeting the lung endothelium (with ACE antibody conjugated liposome) in the endothelial conditional knockout mice. As a centralized and functional core, Core C will perform all mice-related work across all three projects of this program, including generating new strains, breeding and housing of mice, generating preclinical ARDS/VILI models, accessing therapeutic effects of siRNAs and chemicals, performing lung inflammation assessment, and providing tissue samples to individual projects for specific assays (including immunohistochemistry and western blot analysis). In addition to its own space and equipment, the Core will have full access to and will utilize resources available at the University of Arizona shared facilities including the Genetically Engineered Mouse Models Core (GEMM) and the Small Animal Medical Imaging Service (SAMIS) Facility.

Public Health Relevance

ARDS is a devastating and life-threatening syndrome that most commonly occurs as a complication of severe infections and sepsis-induced ARDS is precipitated by an inflammation induced by lipopolysaccharide (LPS) or via ventilator-induced lung injury (VILI). This centralized Core has proven to be excellent on modeling lung injury for the purpose of studying underlying mechanisms and investigating strategies to prevent/treat ARDS studied in this PPG.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL126609-01A1
Application #
9072785
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Arizona
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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