This is an application for a K23 award for Dr. Kirsten Kangelaris, a hospitalist at the University of California, San Francisco. Dr. Kangelaris is establishing herself as a young investigator in patient-oriented clinical research in acute lung injury (ALI), with a focus on understanding biologic and genetic factors that impact susceptibility to and prognosis in acute lung injury among African-American patients. This K23 award will provide Dr. Kangelaris with the support necessary to accomplish the following goals: (1) to become an expert patient-oriented clinical and translational researcher in acute lung injury;(2) to elucidate genetic and biologic mechanisms of acute lung injury combining innovative approaches including genetics, protein markers and functional genomics;(3) to implement advanced biostatistical techniques in clinical studies, including advanced regression and bioinformatics;and (4) to develop an independent clinical research career. To achieve these goals, Dr. Kangelaris has assembled a multidisciplinary team comprised of a primary mentor, Dr. Michael Matthay, who has extensive experience in translational, pathogenesis-oriented ALI research, and in mentoring junior faculty to independent investigators, and two co-mentors: Dr. Elad Ziv, an expert in genetic mapping in admixed populations, and Dr. Bradley Aouizerat, a leader in genomics and molecular epidemiology. Additionally, Dr. Kangelaris will benefit from the expertise of several scientific advisors. Acute lung injury (ALI) is a common cause of acute respiratory failure in hospitalized patients, and African Americans suffer the highest ALI incidence and mortality rates. Dr. Kangelaris'research plan builds on her preliminary data to examine chemokine-dependent pathways of ALI pathogenesis in African-American patients. She will study the role of a functional polymorphism in the Duffy antigen/receptor for chemokines gene (Darc -46C/C, rs2814778), prevalent in individuals of African descent, that has been associated with worse ALI outcomes in her preliminary work, possibly via an increase in circulating interleukin (IL)-8. Dr. Kangelaris will test the extent to which this so-called "Dufy null" genotype is associated with susceptibility to acute lung injury (Aim 1), determine whether the Duffy null genotype is associated with differences in Duffy- binding chemokine levels (e.g., IL-8) and biomarkers of injury among patients with acute lung injury (Aim 2), and to use whole blood gene expression to identify chemokine-related pathways of acute lung injury pathogenesis in African-American patients (Aim 3). This research plan makes use of the existing infrastructure of Dr. Carolyn Calfee's Early Assessment of Renal and Lung Injury (EARLI) cohort at UCSF and Dr. Lorraine Ware's Validation of biomarkers in Acute Lung Injury Diagnosis (VALID) cohort at Vanderbilt University. This research will form the basis for an R01-level application to study the association between chemokine-related genomic and protein markers and acute lung injury susceptibility and outcomes in African-American patients.
Identification of genetic and biologic factors that contribute to acute lung injury pathogenesis among African American patients is the first step in a continuum of research that will pave the way to personalized risk assessment, improved early management and targeted treatments for these patients. Additionally, identification of novel mechanisms of disease in a high risk population will expand our basic understanding of the pathogenesis of acute lung injury relevant in other populations.
|Kangelaris, Kirsten Neudoerffer; Ware, Lorraine B; Wang, Chen Yu et al. (2016) Timing of Intubation and Clinical Outcomes in Adults With Acute Respiratory Distress Syndrome. Crit Care Med 44:120-9|
|Kangelaris, Kirsten Neudoerffer; Ware, Lorraine B; Matthay, Michael A et al. (2016) The authors reply. Crit Care Med 44:e769-70|
|Calfee, Carolyn S; Matthay, Michael A; Kangelaris, Kirsten N et al. (2015) Cigarette Smoke Exposure and the Acute Respiratory Distress Syndrome. Crit Care Med 43:1790-7|
|Sapru, Anil; Calfee, Carolyn S; Liu, Kathleen D et al. (2015) Plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome. Intensive Care Med 41:470-8|
|Kangelaris, Kirsten Neudoerffer; Prakash, Arun; Liu, Kathleen D et al. (2015) Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS. Am J Physiol Lung Cell Mol Physiol 308:L1102-13|
|Sapru, Anil; Calfee, Carolyn S; Liu, Kathleen D et al. (2015) Erratum to: plasma soluble thrombomodulin levels are associated with mortality in the acute respiratory distress syndrome. Intensive Care Med 41:574|
|Calfee, Carolyn S; Janz, David R; Bernard, Gordon R et al. (2015) Distinct molecular phenotypes of direct vs indirect ARDS in single-center and multicenter studies. Chest 147:1539-48|
|Wang, Chen Yu; Calfee, Carolyn S; Paul, Devon W et al. (2014) One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome. Intensive Care Med 40:388-96|
|Kangelaris, Kirsten Neudoerffer; Seeley, Eric J (2014) From storm to suppression in sepsis: are bands the link?*. Crit Care Med 42:2135-6|
|Calfee, Carolyn S; Janz, David R; Bernard, Gordon R et al. (2014) Distinct Molecular Phenotypes of Direct Versus Indirect ARDS in Single and Multi-Center Studies. Chest :|
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