Research & Projects
The goals of my laboratory are to understand how blood vessels, and the endothelial cells that line them, become dysfunctional in critically ill humans. Although blood vessels have numerous importance functions, we are keenly focused on understating endothelial cell regulation of blood volume. Blood volume is maintained by the endothelial barrier. In the setting of overwhelming inflammation or ischemia the endothelial barrier may breakdown allowing fluid and solute to collect in the extravascular space, a clinical entity known as capillary leak. Capillary leak produces organ swelling, tissue dysoxia and ultimately organ failure and death. We are driven to understand these processes, from the patient to the endothelial cells, so we can develop therapies that target blood vessels to improve human health.
Small GTPase regulation of permeability
Small GTPases, namely in the Rho family,regulate key cellular functions, including regulation of tight junction organization in endothelial cells. We investigate how guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) regulate the activity of RhoGTPases (Rho and Rap) with consequences for tight junction integrity.
Regulation of endothelial cell function in critical illness
Blood vessels play an integral role in the progression and resolution of critical illness. We utilize cutting edge techniques leveraged on timely clinical samples to understand blood vessel function and dysfunction across an array of critical illness such as shock, sepsis, ischemia/reperfusion and trauma. We are particularly focused on mediators of capillary leak in critically ill children. These studies are highly translational and focus on mechanisms of vascular dysfunction as well as the discovery of therapeutics to restore normal function.
Acute lung injury
A consequence of pulmonary vascular dysfunction is the accumulation of fluid andimmune cells in the lungs of critically ill children which can lead to respiratory failure. Pulmonary vascular dysfunction can be due to a variety of factors such as infection (bacterial or viral), ischemia reperfusion, trauma or inflammation. We have several ongoing clinical studies of children with viral induced lung injury as well as ischemia/reperfusion injury.
Whole exome sequencing of critically ill children with vascular dysfunction
Working with Yale’s Pediatric Genomic Discovery Program and PGDP Facebook to identify genetic abnormalities that impact the blood vessel response to critical illness. We have previously focused on Systemic Capillary Leak Disease, also known as Clarkson Disease, and are keen to uncover additional genetic abnormalities that impact critically ill children. We welcome physician referrals on behalf of their patients as well as self-referrals from families searching for information about genetic causes for their child’s illness.
For more information please contact: pedsdiscovery@yale.edu.