The overall goal of this renewal application for a Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Ware to continue to build and expand her research and mentoring programs in patient-oriented research in ARDS. This award will allow her to continue to devote significant protected time to her current mentees as well as to expand her mentoring to include new postdoctoral trainees and medical students. In addition, the support of this award will allow Dr. Ware to expand the reach of her mentoring to include new efforts to enhance the mentoring skills of her mentees in order to assure strong mentoring for future generation of patient-oriented researchers. In addition, Dr. Ware's program in patient-oriented research will be expanded in new and novel directions. Specifically, she will focus on how release of cell-free hemoglobin, and genetic heterogeneity in haptoglobin, the primary endogenous scavenger of cell-free hemoglobin, determine the effects of cell-free hemoglobin on primary graft dysfunction, a form of ARDS, after lung transplantation. These studies are based on compelling preliminary data demonstrating that elevated pre-operative plasma levels of cell-free hemoglobin are strongly associated with development of primary graft dysfunction in lung transplant recipients and that the haptoglobin 2:2 genotype is associated with development of ARDS in severe sepsis. There are three specific aims.
Aim 1 will test the hypothesis that plasma cell-free hemoglobin levels are associated with risk of PGD in patients undergoing lung transplantation and that this relationship is modified by FiO2 at reperfusion.
Aim 2 will test the hypothesis that recipient haptoglobin 2:2 genotype is associated with a higher incidence of PGD after lung transplantation and that this relationship is modified by cell-free hemoglobin levels. Finally, Aim 3 will determine the mechanism by which cell-free hemoglobin potentiates the risk of primary graft dysfunction by quantifying biomarkers of lipid peroxidation, endothelial and lung epithelial injury and inflammation and testing their associations with pre- and post-operative cell-free hemoglobin levels and haptoglobin 2:2 genotype. These studies will lead to a better understanding of the influence of cell-free hemoglobin and haptoglobin genotypes on risk of primary graft dysfunction and may lead to improved donor selection criteria and donor-recipient matching. In addition, these studies may lead to new treatments for prevention and treatment of both primary graft dysfunction and non-transplant associated ARDS.

Public Health Relevance

The overall goal of this application is to provide support for Dr. Ware to continue to build and expand her research and mentoring programs in patient-oriented research in acute respiratory distress syndrome, a common cause of acute lung failure. In addition to providing support for mentoring activities, this award will support new research int the causes of acute respiratory distress syndrome after lung transplantation, the most common cause of death in the acute period after lung transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL103836-10
Application #
9918439
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Reineck, Lora A
Project Start
2010-07-09
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
McNeil, J Brennan; Shaver, Ciara M; Kerchberger, V Eric et al. (2018) Novel Method for Noninvasive Sampling of the Distal Airspace in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 197:1027-1035
McKown, Andrew C; Ware, Lorraine B (2018) Pediatric Acute Respiratory Distress Syndrome: Increase the Positive End-Expiratory Pressure? Am J Respir Crit Care Med 198:7-9
Leaf, David E; Siew, Edward D; Eisenga, Michele F et al. (2018) Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients. Clin J Am Soc Nephrol 13:531-541
Brown, Abigail M; Chipps, Teresa M; Gebretsadik, Tebeb et al. (2018) Training the next generation of physician researchers - Vanderbilt Medical Scholars Program. BMC Med Educ 18:5
Van Driest, Sara L; Jooste, Edmund H; Shi, Yaping et al. (2018) Association Between Early Postoperative Acetaminophen Exposure and Acute Kidney Injury in Pediatric Patients Undergoing Cardiac Surgery. JAMA Pediatr 172:655-663
Hughes, Christopher G; Patel, Mayur B; Brummel, Nathan E et al. (2018) Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability. Intensive Care Med 44:345-355
Kuck, Jamie L; Bastarache, Julie A; Shaver, Ciara M et al. (2018) Ascorbic acid attenuates endothelial permeability triggered by cell-free hemoglobin. Biochem Biophys Res Commun 495:433-437
McKown, Andrew C; Brown, Ryan M; Ware, Lorraine B et al. (2017) External Validity of Electronic Sniffers for Automated Recognition of Acute Respiratory Distress Syndrome. J Intensive Care Med :885066617720159
Shaver, Ciara M; Woods, Justin; Clune, Jennifer K et al. (2017) Circulating microparticle levels are reduced in patients with ARDS. Crit Care 21:120
Zhao, Bixiao; Lu, Qiongshi; Cheng, Yuwei et al. (2017) A Genome-Wide Association Study to Identify Single-Nucleotide Polymorphisms for Acute Kidney Injury. Am J Respir Crit Care Med 195:482-490

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