Overview

Cystic fibrosis is best known as a disease of mucus and infection. But many people with CF also carry a heavy burden of allergic, type 2 inflammation including asthma, chronic sinusitis, and allergic bronchopulmonary aspergillosis, and this inflammation predicts worse outcomes. The Cook Lab investigates the molecular reasons why, with a particular focus on the CF protein, CFTR, and the immune cells it controls. We combine human samples, genetically engineered animal models, large-scale "multiomics" profiling, and computational analysis of electronic health records to follow each question from the clinic to the cell and back.

Our research areas span adaptive immunity, innate immunity, T cell biology, and innate lymphoid cell biology.

Current Projects

CFTR as a brake on allergic T cells

CD4+ "Th2" cells fuel allergic disease by secreting IL-4, IL-5, and IL-13. We discovered that T cells themselves express CFTR after activation, and that losing CFTR makes them more sensitive to IL-4 and more prone to becoming Th2 cells. In animal models, CFTR-deficient T cells drive worse allergic airway disease. The CFTR potentiator ivacaftor, a drug already used in the clinic, dampens this inflammation. We are defining exactly how CFTR restrains Th2 development, and whether existing CFTR modulators can be repurposed to treat allergic disease.

Innate lymphoid cells at the onset of inflammation

Group 2 innate lymphoid cells (ILC2s) sit upstream of allergic inflammation and respond to "alarmins" such as IL-33 released by injured airway epithelium. We've shown that CF reprograms the airway epithelium to release more IL-33 and license IL-33–dependent inflammation. We are mapping how CFTR loss rewires the conversation between epithelial cells and ILC2s and identifying new molecular targets that can reprogram ILC2s toward an anti-inflammatory state.

From the electronic health record to the lab bench

Some of our most important clues come from patients. By analyzing large clinical datasets and electronic health records, we've shown that type 2 inflammation in CF is a predictor of mortality and can be targeted with CFTR modulator therapy. We pair these clinical observations with large-scale cellular multiomics to generate testable hypotheses, letting real-world patient data drive basic discovery.

Model systems and approaches

  • Humanized-CFTR and CFTR-deficient mouse models of allergic airway disease
  • Porcine (pig) models of cystic fibrosis
  • Primary human T cells and airway epithelial cultures
  • Single-cell and bulk multiomics (transcriptomics and beyond)
  • Computational analysis of electronic health record data