I am passionate about embryos. Since my teenage years, I was amazed, and still am, by how a single cell can give rise to a complex multicellular organism. The events that occur during development are complicated and require coordination among numerous signals. Any disturbance to the developmental process will lead to abnormal formation of tissues and organs.
The respiratory tract is responsible for gas exchange. For the gas exchange to occur, the air is conducted to the lung's respiratory surface via the upper airways and the conductive airways of the lower respiratory tract. Malformed trachea or bronchi affects the respiratory cycle causing reduced airflow. The condition negatively impacts postnatal lung development at a critical stage when the respiratory tract is in active growth and differentiation.
Airway maladies could have a genetic base. The condition could also be acquired, for example, as a result of invasive ventilation therapies required to help premature babies to breathe. Despite the prevalence and the morbidity of tracheobronchomalacia (TBM), complete tracheal rings (CTR) and tracheal sleeves, current treatments are invasive with causes that are not well understood. A better understanding of the origins of these disorders will lead to novel and more effective therapies to treat infants, children and adults suffering from conditions affecting the trachea and bronchi.
The goal of the Sinner lab is to understand the molecular mechanisms underlying the patterning of the mammalian respiratory tract during normal development and its relevance to congenital disease. Our research interests involve conditions affecting the large airways of the respiratory tract that result from either congenital disabilities or those acquired after injury, including tracheomalacia and CTR.
We are focused on finding answers for four critical questions:
- How does the developing respiratory tract epithelium induce differentiation of mesenchymal lineages, including muscle, cartilage and vasculature of the large airways and the lungs?
- How are the muscle and cartilage established in the developing trachea and bronchi?
- Are there genetic components of human trachea and bronchi malformations?
- How many of the mechanisms/genes identified in the mouse are also mediating trachea and bronchi formation in humans?
At the molecular level, our laboratory focuses on the Wnt signaling pathway and its influence on cross-talk between epithelium and mesenchyme of the trachea necessary for cell differentiation. We are studying how the cartilage and muscle of the trachea are specified and how abnormal Wnt signaling affects tracheal cell differentiation and leads to tracheal malformations. We utilize transgenic mouse models, ex vivo culture systems and live imaging of embryonic tracheal tissue to study the formation of the large airways. In collaboration with physicians and researchers of pulmonary medicine and the Perinatal Institute at Cincinnati Children’s, we are investigating genetic causes of conducting airway malformations in the pediatric population. Thus, the investigations aim to determine the causes of diseases affecting the supporting structure of the trachea and bronchi by comparing mouse and human studies.
One of my labs' discoveries is published in the American Journal of Respiratory and Critical Care Medicine. The paper was the first study examining the causes of complete tracheal ring deformity (CTRD) in humans. The exome sequences of children with CTRD and their biological parents identified somatically and inherited gene variants in patients with CTRD comprising a molecular signature of altered Hedgehog (Hh) and Wnt signaling in patients with CTRD. Genetic manipulation of murine homologs required for tracheal development in mice was used to validate the relevance of the human gene variants identified in patients with CTRD "Complete Tracheal Ring Deformity: A Translational Genomics Approach to Pathogenesis" Am J Respir Crit Care Medicine.
Another important discovery is published in Developmental Biology. The significant finding in this paper is that Wnt ligands produced by the tracheal epithelium, pattern the tracheal mesenchyme via modulation of gene expression, required for tracheal cartilage and smooth muscle differentiation "Endodermal Wnt signaling is required for tracheal cartilage formation" Developmental Biology.
I’m honored to have received the A. Basil O' Connor Starter Scholar Research Award from the March of Dimes (2012) and the Excellence in Undergraduate Research Mentoring in Science, Technology, Engineering, or Math, Experience-Based Learning and Career Education award from the University of Cincinnati (2019).
I have been a researcher for more than 22 years and began working at Cincinnati Children's in 2003. I enjoy mentoring students in the lab and making them aware of the relevance of congenital disabilities. I have experience working with different model organisms, including rats, mice and frogs. I’m delighted by the fact that the research I pursue contributes to improving the health of children.
Developmental biology; lung development; congenital defects
Assistant Professor, UC Department of Pediatrics
Neonatology, Pulmonary Biology