This application for a Mentored Clinical Scientist Research Career Development Award (K08) addresses the important issue of racial disparities in both risk and severity for acute respiratory distress syndrome (ARDS), a severe acute critical illness with a high mortality rate (~30%) affecting up to 200,000 US patients each year. Subjects of African descent exhibit increased ARDS risk and higher ARDS mortality compared with non- Hispanic whites. It has been increasingly appreciated that genetic factors participate in determining predisposition to ARDS and may contribute to observed health disparities. Additionally, an understanding of genetic determinants of ARDS susceptibility will hasten the development of novel personalized preventive and therapeutic approaches to ARDS care. The PI for this K08 application is an Assistant Professor of Medicine at the University of Arizona who aspires to a career focused on translational ARDS research related to deciphering the genetic and non-genetic factors that underlie the observed health disparities in critical care and to exploring personalized therapies in ARDS. The PI has clinical training in pulmonary and critical care medicine, as well as training and experience in the design and conduct of clinical trials. He now proposes to extend the reach and scope of his research towards a translational systems biology program in ARDS and critical care. Under the mentorship of Joe GN Garcia MD, a world-renowned physician-scientist in the field of ARDS, genetics, and health disparities, the PI has generated important preliminary data implicating the selectin P ligand (SELPLG) gene and its encoded protein, P-selectin glycoprotein ligand 1 (PSGL1) as novel susceptibility targets for ARDS in individuals of African descent. The proposed research will employ a focused and comprehensive systems biology approach to test the hypothesis that SELPLG and PSGL1 are novel ARDS targets with genetic variants that confer ARDS susceptibility.
Specific Aim #1 (SA #1) will characterize the regulation of SELPLG expression by ARDS stimuli and carefully-selected SELPLG promoter SNPs on SELPLG gene promoter activity SA #2 will characterize effects of SELPLG coding SNPs on PSGL1 activity in preclinical models of ARDS. Finally, SA #3 will assess the association of selectin pathway gene SNPs with ARDS risk and mortality utilizing the Sequenom MassARRAY genotyping platform on a diverse well- phenotyped cohort of ARDS patient DNA samples (>2,000) and healthy controls (race-matched) from the DNA repository stored within our University of Arizona biobank. Thus, the K08-suported training in advanced genetics, functional genomics, bioinformatic analysis, and lung injury biology, will have high translational therapeutic implications and will enhance the likelihood that the PI will successfully transition to an independent research career focused on translational ARDS and health disparities.
Racial disparities in Acute Respiratory Distress Syndrome (ARDS), a devastating consequence of systemic inflammatory conditions (such as sepsis) that afflicts an estimated 200,000 people a year in the US, are well established, especially for patients of African descent. Genetic factors likely contribute in determining predisposition to ARDS and might explain observed health disparities. This proposal seeks to better understand the role of P-selectin glycoprotein ligand 1 (PSGL1, SELPLG gene) in leukocyte recruitment to the site of inflammation during pulmonary vascular leak, and the genetic influences of variants in this gene that may contribute to observed racial disparities and eventually lead to the development of precise, individualized therapies for patients with ARDS.
