The Garcia laboratory is a state of the art pulmonary research lab focusing on the genetics and proteomics of lung biology and disease. Our goal is to understand the molecular mechanisms of lung inflammatory processes, particularly those producing lung edema or vascular leak. The laboratory encompasses a mosaic of specialized talents to investigate all aspects of research including gene discovery, protein function assessment, SNP discovery, genetic manipulation, in vivo testing, and candidate gene and biomarker identification. Using this bench-to-bedside approach, we hope to translate our basic research into potential novel clinical therapies.
Vascular leak occurs when blood cells and fluid escape from blood vessels into the surrounding tissues, including the lungs. This follows acute injury or infection and occurs in response to the stresses of mechanical ventilation. Acute lung injury is a complex illness with high mortality rate (> 35%) and often requires the use of mechanical ventilator support for respiratory failure. Mechanical ventilation can lead to clinical deterioration due to augmented lung injury in certain patients, suggesting the potential existence of genetic susceptibility to mechanical stretch, the nature of which remains unclear. When severe, flooding of the lungs often leads to organ damage or death.
Our studies of the basic biology of this process have focused on signal transduction pathways and the cytoskeleton of the endothelium. The Garcia laboratory was the first to clone the non-muscle myosin light chain kinase (nmMLCK) gene and demonstrate the importance nmMLCK in actin-cytoskeleton reorganization of vascular endothelial cells (EC) during inflammatory response. In addition, our lab was the first to report that sphingosine 1-phosphate (S1P), an angiogenic sphingolipid produced in platelets, has potent barrier-enhancing properties that can maintain endothelial barrier function and reverse endothelial barrier dysfunction via activation of cortical actin cytoskeleton involving nmMLCK and cortactin. We have demonstrated in mouse, rat, and canine models of lung injury that S1P can effectively attenuate acute lung injury from a variety of insults such as ventilator-induced lung injury (VILI), radiation-induced lung injury (RILI), and endotoxin-induced lung injury. We are currently exploring the use of FTY720, a multiple sclerosis Phase III clinical trial drug which has structural resemblance to S1P, as treatment for ALI along with various FTY720 analogues. Also, using microarrays to probe RNA from pathophysiological stretched EC, our lab identified Pre-B cell colony enhancing factor (PBEF, aka NAMPT or visfatin) as a novel biomarker for inflammatory response and developed an anti-PBEF antibody treatment for neutralizing extracellular-secreted PBEF. Other novel therapeutic agents include simvastatin, ATP, HMW-polyethylene glycol, HMW-hyaluronan, methylnaltrexone, activated protein C, and sorafinib.
Our lab has also identified genetic differences in key proteins that increase disease susceptibility. Certain single nucleotide polymorphisms (SNP) in proteins such as MLCK, cortactin, and PBEF confer to increased genetic susceptibility in particular patient populations. We are creating a multi-institution bio-bank of patient samples from various diseases (including ALI/ARDS, sickle cell disease, pulmonary hypertension, idiopathic pulmonary fibrosis, sarcoidosis, radiation pneumonitis, ischemia/reperfusion from lung transplantation) to study these genetic susceptibilities. This bio-bank, along with the genetic and proteomics analysis of lung biology and disease, should provide new insights into pathogenesis and treatment of these diseases.