The overall goal of this Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Ware to build and expand her research and mentoring programs in patient-oriented research in acute lung injury (ALI). This award will allow her to devote more time to her current mentees as well as to expand her mentoring to include new postdoctoral trainees as well as medical students in the Vanderbilt Emphasis Training Program. In addition, the support of this award will allow Dr. Ware to assume an important role as Co-Director of the T32 Clinical and Translational Research Training Program in Pulmonary Medicine training program (NIH 5T32 HL087738). Dr. Ware's program in patient-oriented research will be expanded in new and novel directions. Specifically, she will build on studies of organ donors and ALI (primary graft dysfunction, PGD) after lung transplantation, as well as ongoing studies of the mechanistic role of alterations in coagulation and fibrinolysis in ALI. PGD has a major impact on morbidity, mortality and cost of lung transplantation. Studies of PGD are unique in the field of ALI research in their potential to determine the impact of intrinsic donor-derived lung factors on the pathogenesis of ALI. The overall hypothesis of the proposed studies is that alterations in the coagulation and fibrinolytic cascades at both the genetic and protein level in the donor lung are major determinants of PGD in the lung allograft recipient. This hypothesis will be tested in two specific aims:
Specific Aim 1 : To test the hypothesis that there is a significant association between common polymorphisms in coagulation and fibrinolysis genes in the organ donor and clinical outcomes in the lung transplant recipient, including PGD. These studies will also test the association of donor plasma levels of the protein products of the genes whose polymorphisms are associated with worse or better clinical outcomes.
Specific Aim 2 : To test the hypothesis that there is a differential contribution of dysregulated coagulation and fibrinolysis in organ donors compared to organ recipients to recipient clinical outcomes including PGD. A better understanding of the influence of the coagulation and fibrinolytic pathways in the donor lung on subsequent development of PGD in the lung recipient will significantly enhance our understanding of the pathogenesis of ALI and may ultimately lead to new therapies for prevention and treatment of PGD in lung transplant recipients as well as potential new therapies for non-transplant associated ALI. These studies may also lead to improved donor selection criteria and donor-recipient matching to reduce the incidence of PGD. The better understanding of disease pathogenesis and improved early diagnosis that will be realized through patient-oriented research and a well trained new generation of clinical researchers in ALI will deepen our knowledge and open up new therapeutic opportunities for this clinical disorder that affects 200,000 Americans annually with a mortality rate of approximately 40%.

Public Health Relevance

Studies of PGD are unique in the field of ALI research in their potential to determine the impact of intrinsic donor-derived lung factors on the pathogenesis of ALI. The overall hypothesis of the proposed studies is that alterations in the coagulation and fibrinolytic cascades at both the genetic and protein level in the donor lung are major determinants of PGD in the lung allograft recipient.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL103836-02
Application #
8109358
Study Section
Special Emphasis Panel (ZHL1-CSR-R (M1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2010-07-09
Project End
2015-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2011
Total Cost
$161,445
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Shaver, Ciara M; Ware, Lorraine B (2017) Primary graft dysfunction: pathophysiology to guide new preventive therapies. Expert Rev Respir Med 11:119-128
Famous, Katie R; Delucchi, Kevin; Ware, Lorraine B et al. (2017) Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med 195:331-338
Luo, Liang; Shaver, Ciara M; Zhao, Zhiguo et al. (2017) Clinical Predictors of Hospital Mortality Differ Between Direct and Indirect ARDS. Chest 151:755-763
Russell, Derek W; Janz, David R; Emerson, William L et al. (2017) Early exposure to hyperoxia and mortality in critically ill patients with severe traumatic injuries. BMC Pulm Med 17:29
McKown, Andrew C; McGuinn, Erin M; Ware, Lorraine B et al. (2017) Preadmission Oral Corticosteroids Are Associated With Reduced Risk of Acute Respiratory Distress Syndrome in Critically Ill Adults With Sepsis. Crit Care Med 45:774-780
Hamilton, B C S; Kukreja, J; Ware, L B et al. (2017) Protein biomarkers associated with primary graft dysfunction following lung transplantation. Am J Physiol Lung Cell Mol Physiol 312:L531-L541
Murphy, Laura S; Wickersham, Nancy; McNeil, J Brennan et al. (2017) Endothelial glycocalyx degradation is more severe in patients with non-pulmonary sepsis compared to pulmonary sepsis and associates with risk of ARDS and other organ dysfunction. Ann Intensive Care 7:102
Shaver, Ciara M; Woods, Justin; Clune, Jennifer K et al. (2017) Circulating microparticle levels are reduced in patients with ARDS. Crit Care 21:120
Sapru, Anil; Liu, Kathleen D; Wiemels, Joseph et al. (2016) Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome. Crit Care 20:151
Hughes, Christopher G; Pandharipande, Pratik P; Thompson, Jennifer L et al. (2016) Endothelial Activation and Blood-Brain Barrier Injury as Risk Factors for Delirium in Critically Ill Patients. Crit Care Med 44:e809-17

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