Projects | Brewington Research Lab

Conducting Research to Achieve Our Goals

We currently have several related projects in process, primarily focusing on cystic fibrosis (CF). These projects span from pure basic science to clinical studies, with most touching the lab and the clinic at some point. In addition, our lab operates core services that provide translational resources and support to other investigators and collaborators.

Development of Nasal Cell-Based Respiratory Research Models

Lower airway cell models have been a mainstay of respiratory research for decades. These cells, harvested from lung explants after transplant or patient death, are a valuable tool as primary human cells, but becoming more limited in availability over time. Nasal cells, on the other hand, are easy to obtain from any patient, and may serve a similar role in research. Traditionally nasal cell culture was limited, but new culture techniques allow us to grow brushed nasal cells into models for study. We seek to understand the fidelity of these models to the traditional models, and the resolution of model data to their individual patient source. Previous and ongoing work in this area includes:

Development and validation of nasal cell-based organoids to quantify CFTR function
Optimization of traditional air-liquid interface cultures in nasal cells
Comparison of nasal cell cultures to bronchial cell cultures as a group and from the same patient
Similarities and differences in the transcriptome of nasal and bronchial cell cultures in disease and health
Generation of normative data for CFTR function in cultures from individuals with and without CF

Patient-Specific Theratyping in CF

The term “theratyping” in the CF community has emerged to describe the process of asking “what therapy would work for this patient?" There are many ways to perform theratyping in CF, including cell lines and high-throughput screening. Our group focuses on using patient-derived models (nasal cells) to determine CFTR modulator treatment response in patients with CF and rare CFTR genotypes. This work is supported by the CF Foundation through a National Resource Center award and is enrolling subjects with rare CFTR genotypes throughout the United States, with hundreds of patients involved to date. Previous and ongoing lines of work include:

Validating drug-induced changes in nasal cell models as a predictor of patient benefit with therapy in common genotype groups
Optimizing protocols for remote cell collection and shipping, processing, and growth of cell models
Linking model responses to clinical benefit in individuals with rare CFTR variants
Sharing protocols and experience with collaborators establishing local theratyping centers
Advocacy for off-label insurance coverage in individuals with biologic evidence of therapeutic benefit

Mechanisms of Disease and Therapeutic Response Variance in CF

Previous studies have demonstrated that approximately 50% of disease variance in CF is due to factors beyond the CFTR genotype, including other genetic changes, environmental exposures, airway bacterial colonization, and more. The molecular mechanisms underlying this variance is unclear, even in cases where genetic modifiers are known. The same baseline disease variance is mirrored in responses to CFTR modulator responses, with patient benefits ranging from minimal to extraordinary even among those with the same genotype. We seek to use our experience in patient-specific disease modeling to understand this variance to optimize care delivery. Ongoing work includes:

Quantifying non-CFTR specific ion transport as a molecular modifier of cell physiology
Understanding the cellular impact of known genetic modifiers of CF disease severity
Enrolling high- and low- responder groups for clinical and cell-based studies to identify novel differences
Transcriptional profiling and mechanistic studies of cell-based models before and after treatment with CFTR modulators

Translational Study Support

In addition to our hypothesis-driven research, the Brewington lab supports translational studies in respiratory disease locally and across the country. This includes diverse support from consultation/sharing of protocols, to sample processing/analysis, to linking patient specimens to clinical information, and more. These studies are funded in part by the CCRF, the CF Foundation, and the NIH. Mechanisms of support include:

Collection/analysis of relevant clinical trial endpoints (e.g., spirometry, sweat chloride, lung clearance index, etc.)
Nasal Potential Difference (NPD) for diagnosis of CF or CF clinical trials
N-of-1 clinical trial support and therapeutic response phenotyping
Banked respiratory samples including >2,000 pediatric bronchoalveolar lavage fluid specimens
Prospective trial support including patient specimens linked to clinical data
Respiratory cell model generation, analysis, banking, and/or sharing for mechanistic studies

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