P01HL151327

Macrophage Plasticity in Inflammatory Lung Injury - Research Summary/Abstract of Program

The fundamental challenge in treating the hyper-inflammatory state underlying Acute Lung Injury/Acute Respiratory Distress Disorder (ALI/ARDS) is that broad anti-inflammatory interventions could compromise host defense and potentially exacerbate the underlying infectious process that triggered ALI/ARDS. Novel targeted approaches to treat ALI/ARDS thus require an in-depth understanding of the intricate inflammatory mechanisms to reduce the extent of injury and promote the resolution of inflammation as well as the initiation of lung repair without compromising host defense.

It is now recognized that macrophages (MF) in lungs represent diverse multi-functional cell populations. They have the ability to sense pathogens and danger signals, and their plasticity and diversity allows them to respond in specialized manners to specific niche environments. They are able to change their phenotypes in a chameleon-like manner by activation of specialized transcriptional programs. Thus, they have the remarkable ability to amplify inflammation and also to coordinate resolution of lung inflammatory injury and restore homeostasis. MF carry out these functions through the release of an array of cytokines, phagocytosis of microbes, efferocytosis of dead cells, and provide the essential inflammatory or reparative signals to nearby cells.

The central focus of this program will be to precisely define the roles of distinct macrophage subpopulations in inflammatory lung injury and signaling nodes to harness the plasticity of macrophages and thereby bring about the resolution of lung injury.

Project 1 will test the hypothesis that two specific ion channels, P2RX7 (purinergic receptor 2 subtype X7) and the potassium (K+) efflux channel TWIK2 regulate the plasticity to either promote lung injury or to activate the repair program.

Project 2 will test the hypothesis that the transcription factor CREB and its downstream targets are critical regulators of the anti-inflammatory and reparative function of alveolar MF.

Project 3 will test the hypothesis that endothelial cells lining all lung vessels direct the plasticity of MF via modulation of WNT signaling in MF.

Project 4 will test the hypothesis that circulating postnatal CX3CR1+ monocytes replenish lung interstitial MF during inflammatory injury and can direct the lung tissue repair program.

These four projects are supported and complemented by highly innovative scientific cores which will provide important optogenetic tools (Synthetic Biology and Optogenetics Core B), super-resolution and intravital imaging (Advanced Imaging Core C), and access to clinical samples as well as single cell transcriptomic analysis of macrophages (Clinical Sampling and Genomics Core D) to unravel the complexities of macrophage biology in lung injury, thus paving the way for much-needed novel therapeutic approaches in ALI/ARDS.

University Of Illinois

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 60612 United States

Single Zip Code

NHLBI Program Project Applications (P01 - Clinical Trials Optional) (PAR-18-405)

Amendment Since initial award the total obligations have increased 418% from $2,281,477 to $11,822,456.