Assistant Professor of Medicine
Pulmonary, Cirtical Care and Sleep Medicine and the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research
Keck School of Medicine
- Stem Cells
- Regenerative Medicine
- Lung Biology
- Cystic Fibrosis
- Epithelial Cells
- Gene Editing
- Cell Therapy
Research OverviewResearch in my lab focuses on using stem cells as a tool to study human lung biology in health and disease and as a potential therapeutic/diagnostic approach for patients with lung diseases. We use patient derived induced pluripotent stem cells (iPSC) to generate models of lung disease such as cystic fibrosis (CF), idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and ciliopathies. We combine state-of-the-art gene editing (CRISPR) and iPSC technologies with directed differentiation, proteomics, epigenetics and next-generation sequencing to: 1) generate reproducible models of respiratory diseases in a dish; 2) generate chimeric animal models to understand disease development and progression; and 3) utilize these models in high-throughput screening.
Ongoing Projects Include:
1) Mecianisms of Lineage Specification and Regulation in the Developing Human Lung.
Human lung disease remains one of the highest causes of morbidity and mortailty in the world today. Death rates are increasing, drug candidates have a high failure rate and fewer new therapies are making it to market than for other common diseases. My lab developed a methodology for taking pluripotent stem cells (PSC) and directing them to generate mature lung epithelial cells. We are using, and further developing, this as a tool to:
- Study PSC fate specification to proximal airway cells (Club, Basal, Multiciliated and Goblet cells) and distal airway cells (Alveolar Type I and II)
- Study disease causing mutations during lung development
- Identify novel cell surface markers and to isolate and expand specific populations of pulmonary epithelial cells.
2) Developing Stem Cell Therapies for Cystic Fibrosis.
CF remains the most lethal autosomal recessive disorder in Caucasians, affecting around 70,000 people worldwide. Although multiple organs are affected it is the pulmonary manifestations that are the primary cause of CF related morbidity and mortality. Despite the identification of almost 2000 disease causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), the precise role of CFTR in the development and progression of CF lung disease is still poorly understood. This is largely due to a lack of in vivo/in vitro models that closely reflect human lung development and CF pathology. We are working on:
- Development of patient specific iPSC based models and high throughput screening tools for CF
- Generation of an expandable and transplantable population of lung stem cells from iPSC with the capacity for regeneration of an injured lung utilizing the ferret as a pre-clinical model
3) Understanding Multiciliated Cell Development and Regulation in Health and Disease
Mucociliary clearance is an essential function to prevent chronic airway disease. In the healthy lung, multiple motile cilia beat synchronously to transport inhaled particles and mucus out of the airways. Poor mucociliary clearance is a fundamental feature of many inherited and acquired respiratory diseases including reduced generation of multiple motile cilia syndrome (RGMC), primary ciliary dyskinesia (PCD), asthma, chronic bronchitis and CF. PCD is a rare (1:15 000) condition resulting in recurrent respiratory tract infections and progressive lung damage. Supportive care provides the only therapeutic option. In order to develop effective treatments for these diseases characterized by ciliary dysfunction, we need to understand the cellular signaling components that lead to their initiation, development and progression specifically focusing on multiciliated cells. We are working on:
- Dissecting the cellular and molecular pathways influenced by known genetic mutations leading to the development of ciliopathies.
- Understanding the role of CFTR in human airway development, particularly the role in multiciliated cell development