R01HL159494

Emulating Immune Dysregulation by Trisomy 21 in a Multi-Organ-on-a-Chip System

Trisomy 21 (T21) is the molecular cause of Down Syndrome (DS), the most common chromosomal abnormality in humans worldwide. Lung disorders represent an important cause of morbidity and mortality in people with DS. Recurrent respiratory infections are particularly common in these individuals and are often life-threatening. However, despite recent studies reporting immune dysregulation and interferon hyperactivity in individuals with DS, there is a critical gap in our understanding of how extra genetic material from chromosome 21 influences the homeostatic immune activity of the lung, and innate immune activation and mobilization of myeloid leukocytes, which are key mediators of acute immune response to respiratory pathogens.

Organs-on-chips are biomimetic, microfluidic, cell culture devices created with microchip manufacturing methods that contain continuously perfused hollow microchannels inhabited by living tissue cells arranged to simulate organ-level physiology. By recapitulating the multicellular architectures, tissue-tissue interfaces, chemical gradients, mechanical cues, and vascular perfusion of the body, these devices produce levels of tissue and organ functionality not possible with conventional two-dimensional or three-dimensional culture systems. They also enable high-resolution, real-time imaging and in vitro analysis of biochemical, genetic, and metabolic activities of living cells in a functional tissue and organ context.

The overarching goal of this project is to apply microengineering principles of organ-on-chip technology and develop a highly innovative and advanced, physiologically relevant model of organ-organ crosstalk to delineate the impact of DS on the homeostatic physiology of the lung and emulate clinically observed immune dysregulation due to T21. For this, we will create a microfluidically integrated murine multi-organ system that reproduces the bone marrow (BM)-lung axis, using primary cells isolated from wild-type (WT) and OP(16)1/YEY mice (a murine model of DS).

In parallel, to enable eventual translation of findings to humans, we will focus part of our efforts on generating human lung airway epithelia, vascular endothelium, and hematopoietic stem cells from induced pluripotent stem cells of healthy subjects and individuals with DS to recreate lung and BM tissue in the integrated multi-organ chip system. We will utilize these murine and stem cell-based platforms to study how T21 affects the normal functioning and biological responses of the lung airway epithelium and endothelium. Moreover, we will analyze in real-time the development of inflammation and the mobilization of innate immune cells in response to challenge with inhaled airborne influenza virus particles.

Our central hypothesis is that this dynamic living microsystem can recapitulate innate immune dysregulation in DS, reveal a pulmonary exaggerated immune response to challenge with inhaled infective agents, and enable the discovery of previously unknown pathologies in airway function in the context of a multi-organ physiologically linked system.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

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]

Pennsylvania United States

State-Wide

Transformative Research Award for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project (R01 Clinical Trial Not Allowed) (RFA-OD-20-005)

Amendment Since initial award the End Date has been extended from 07/31/24 to 07/31/26 and the total obligations have increased 74% from $2,101,852 to $3,649,414.