UNLOCKING THE GENETIC CODE TO THE HEART AND LUNG DISEASES.

PROJECTS

Discovering new genes and signaling pathways essential in cilia assembly and function.

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 from heart, respiratory to skeletal and metabolic diseases. We have projects focused on identifying novel genes and signaling pathways essential in cilia assembly and function in the context of tissue and organ development.

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 translated into chemical signals 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 and yet, the rate of genetic diagnosis remains very low. We are addressing this shortcoming by developing and implementing high-throughput functional genomics models of frog embryos and human airway 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.

Bench to Bedside PRECISION MEDICINE program for 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 basic science and clinical expertise in functional genomics human genome analysis , genetic counseling, pediatric cardiology, and pediatric pulmonology 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.