R01HL159558

Targeted Gene Delivery Systems Treating Lung Diseases - Project Summary

This R01 proposal outlines a research plan which uses targeted nanomedicine to enhance disease-modifying molecular mechanisms both in the acute injurious phase and in the subsequent chronic fibrotic phase of viral-induced pneumonitis. The overall goal of this proposal is to use nanomedicine to modify specific cellular subtypes during the lung disease process.

Acute and chronic lung diseases are major causes of mortality and morbidity in the US. Acute respiratory distress syndrome (ARDS), caused by widespread endothelial barrier disruption and uncontrolled cytokine storm, is the major cause of death in critically ill influenza and COVID-19 patients. Furthermore, pulmonary fibrosis, progressive scarring in injured lung, is a major sequelae of viral pneumonia. Early analyses showed that discharged COVID-19 patients are at high risk for developing pulmonary fibrosis.

Currently, there are few pharmacological treatments that directly target ARDS, and available therapeutic options for pulmonary fibrosis remain suboptimal, underscoring unmet medical needs in a heightened state due to the COVID-19 pandemic. Strongly supported by our published and unpublished in vivo results, we believe that targeted nanomedicine approaches have tremendous potential to treat ARDS and pulmonary fibrosis, which will be comprehensively tested in vivo in this application.

Aim 1 will test the therapeutic effectiveness of specifically reducing endothelial dysfunction in acute lung injury (influenza or SARS-CoV-2) in mice and perfused human lungs using a VCAM1-targeting, KLF2 mRNA-encapsulated nanoparticles. We anticipate that specific endothelial KLF2 overexpression will reduce acute lung injury.

Aim 2 will test the therapeutic effectiveness of specifically targeting lung fibroblasts in chronic pulmonary fibrosis (bleomycin) in mice and human lung slices using PDGFRB-targeting nanoparticles to deliver shRNAs against TXNDC5. We anticipate that specific fibroblast inhibition of TXNDC5 will reduce lung fibrosis.

University Of Chicago

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Chicago, Illinois 606375418 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 298% from $797,003 to $3,172,072.