TRANSLATIONAL GENOMICS OF CARDIAC, PULMONARY AND NEUROLOGICAL DISORDERS.

PROJECTS

Discovering new genes and signaling pathways essential in cilia assembly and function in heart, lung, and brain development.

Cilia are microtubule-based organelles present on almost all the cells in the human body and serve multiple roles during development and homeostasis. Defects in the assembly or function of cilia can lead to an array of diseases, including congenital heart disease (cardiac), primary ciliary dyskinesia (pulmonary), and hydrocephalus and autism (neurological) disorders. We have projects focused on identifying novel genes and signaling pathways essential in cilia assembly and function in heart, lung, and brain development. Our research directly contributes to improving the depth of gene panels used for the genetic diagnosis of these birth defects.

Uncovering the mechanochemical gene regulatory networks (GRNs) in lung development and function.

Mechanical forces play a critical role in respiratory physiology. Our lungs continuously expand and compress as we breathe, exerting mechanical tension on the lung epithelium. This mechanical tension is essential for the differentiation of airway and lung epithelial cells (multiciliated cells, mucus-secreting cells, ionocytes, etc.). We have projects focused on uncovering mechanochemical GRNs essential for proper cell differentiation and maintaining epithelium integrity in the airway and lungs.

High-throughput translational genomics of pulmonary disorders.

Respiratory diseases (RDs) are caused by defects in the structure or function of motile cilia and multiciliated cells in the airway and lungs. These patients are at risk of recurrent respiratory infections, bronchiectasis, or even respiratory failure. About half of all these patients also develop cardiac defects. RDs are often challenging to diagnose due to the lack of a “gold standard” diagnostic tool and clinically variable presentation. Genetic testing has the potential to address these shortcomings. It can help identify patients who need functional assessment and improve the diagnostic process, thus impacting the need to diagnose patients at an early age. Next-generation sequencing (NGS) has identified about 60 genes, and about 1800 variants are classified as pathogenic. Yet, the rate of genetic diagnosis remains very low because an additional 10,000 variants remain of unknown significance (VUS) and a significant burden on RD diagnosis. We are addressing this shortcoming by developing and implementing high-throughput functional genomics models of frog embryos and human lung cell culture to classify variants robustly and at an unprecedented rate. Our research has an immediate positive global impact by increasing the rate of genetic diagnosis in RD patients in a clinically consequential time frame.

High-throughput translational genomics of congenital heart disease (CHD).

CHD is a leading cause of infant death. Nearly 1 in 100 babies are born with a heart defect, and about 25% have critical CHD. CHD remains a leading cause of infant death because phenotypically similar patients can have dramatically different outcomes. Therefore, we need clinical treatment driven by the genotype instead of a phenotype to treat these patients effectively. The NGS has identified candidate disease variants rapidly and cost-effectively. However, the yield of current clinical genetic testing is less than 30%, and determining the pathogenicity of the remaining candidate genes remains a major obstacle. Dr. Kulkarni has established a Bench-to-Bedside (B2B) CHD program at UVA Children’s to address this challenge. Our B2B project brings together experts in functional genomics (Dr. Kulkarni), genomic bioinformatics analysis (Dr. Ratan), genetic counseling (Mr. Thomas), pediatric cardiology (Dr. Peroutka and Dr. Haregu), and pediatric pulmonology (Dr. Garrod) to facilitate patient-driven research. Our research directly helps patients and families with aggressive management of clinical complications, including the risk of developing life-threatening conditions like respiratory problems and hydrocephalus. Further, our research enables recurrence risk counseling and reproductive decision-making for parents.

High-throughput translational genomics of neurological disorders.

NGS has identified hundreds of candidate genes and thousands of variants in neurological disorders like hydrocephalus and autism. However, their role in causing these disorders is not characterized. We address this unmet clinical need by functionally classifying these candidate genes and variants as pathogenic or benign to increase the diagnostic rates of these neurological disorders. Mouse is too slow and costly for the rapid functional classification of hundreds of variants. Therefore, we use frogs to functionally characterize these genes and variants in the context of brain development first. Analyssi in frogs is followed by mouse and human cell culture and organoid models for selective candidates. Our research has an immediate positive global impact by increasing the rate of genetic diagnosis in patients with hydrocephalus or autism.