R01HL155104

Type I IFN Signaling During Lung Development in Down Syndrome - Project Summary/Abstract

Down Syndrome (DS), also referred to as Trisomy 21, is the most common human chromosomal anomaly, affecting 1 in 700 live births. Although DS can affect many organ systems, lung and heart disease are the leading causes of morbidity and mortality. Several congenital lung anomalies are reported in individuals with DS, including airway branching defects, with a 25% decrease in the number of branches and reduced upper airway muscle tone with dysphagia and/or bronchomalacia. These complications remain constant into adulthood, as opposed to becoming exacerbated, and are hence likely due to developmental insufficiency.

While abnormal pulmonary structure and function in pediatric and adult DS subjects has been described, there is limited data defining the ontogeny of these abnormalities. We postulated that some developmental differences could initiate prenatally. Preliminary data developed for this application shows that DS fetal lungs, starting as early as 16 weeks gestation, present with pronounced dilatation of terminal airways/acinar tubules, dilated lymphatics, and muscularized arteries. In addition, we find increased lung expression of type I IFN signaling target genes such as MX1 and IFI27 in DS compared to non-DS fetal lungs. IFN signaling plays a critical role in cell differentiation, proliferation, apoptosis, and ECM production, important events for lung development. Finally, our preliminary data show that DS lungs exhibit altered expression of ECM affiliated proteins, regulators, and secreted factors (FN1, COL6, etc.). Therefore, we hypothesize that lung defects in DS can initiate during fetal development, and that IFN-dependent changes in cell proliferation, differentiation, and ECM production contribute to these defects.

To test this hypothesis, we will:

1) Test the hypothesis that morphological, cellular, and molecular abnormalities are initiated during the late pseudoglandular/early canalicular stages of fetal development in DS lungs using histopathological analyses and single-cell sequencing.

2) Test the hypothesis that excessive type I IFN signaling disrupts cell differentiation and airway branching during fetal lung development in DS.

3) Test the hypothesis that excessive IFN signaling disrupts ECM production during fetal lung development in DS.

For aims 2 and 3, we will use our published fetal lung explants culture model as well as epithelial organoid cultures alone or co-cultured with mesenchymal cells to test the effect of gain and loss of function of type I IFN signaling on cell differentiation and ECM production.

These studies have the promise to improve our understanding of the key molecular and cellular differences, and the mechanisms controlling branching defects in DS developing lungs. The innovative aspects of this work are likely to have great overall impact and facilitate the translational potential for therapies for DS individuals, as well as other lung congenital defects demonstrating hypoplastic lungs.

Lundquist Institute For Biomedical Innovation At Harbor-Ucla Medical Center

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.

93.310 - Trans-NIH Research Support

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

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Torrance, California 905022006 United States

Single Zip Code

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

Amendment Since initial award the End Date has been extended from 06/30/24 to 06/30/26 and the total obligations have increased 81% from $1,805,958 to $3,274,532.