This proposal outlines a five year training plan culminating in a career as an independent translational investigator within the field of lung transplantation. The applicant has completed his subspecialty training in pulmonary and critical care medicine at UCLA. Having identified academic medicine as a career goal, the Depaiiment of Internal Medicine and the Division of Pulmonary and Critical Care have committed to the applicant's career development. The applicant's training has included more than 24 months of protected time for research spanning the final 2 years of fellowship and as a junior faculty member since July, 2007. The applicant completed a Master of Science degree in clinical research in June 2008. The training plan in this proposalincludes additional didactics in biostatistics and in immunology. John Belperio, an experienced translational investigator in lung allograft rejection, will serve as the prirnary scientific mentor. Robert Elashoff, a renowned biostatistician and expert in clinical trial design, will serve as a co-hnentor. Chronic lung allograft rejection, also known as bronchiolitis obliterans syndrome (BOS), is the most important factor limiting long term survival in lung transplant recipients. While acute rejection is the primary risk factor for BOS, numerous infections have also been implicated. Our preliminary data suggest a novel association between Aspergillus ainway colonization and the'development of BOS. Additional preliminary exploratory studies have identified a possible mechanism involving CC chemokine mediated recruitment of lymphocytes to the ainway, which is a precursor to the development of BOS. This proposal includes an observational study of sequential cohorts involving either targeted or aggressive antifungal prophylaxis.
The specific aims of this study include: 1) Determine the effectiveness of aggressive anti-fungal prophylaxis at reducing the incidence of Aspergillus colonization;2) Determine the effectiveness of aggressive anti-fungal prophylaxis at reducing the development of BOS;and 3) Determine the biologic mechanism responsible for the Aspergillus/BOS association.

Public Health Relevance

^. The median survival after lung transplantation is only 5 years, priamrily due to BOS. There is no proven treatment for BOS, elevating the importance of prevention. Aspergillus colonization occurs in 1/3 of lung transplant recipients. Demonstration that a reduced incidence of Aspergillus colonization using prophylaxis results in a lower risk of BOS would quickly translate to improved outcomes for lung transplant patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-R (M1))
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Colombini-Hatch, Sandra
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Weigt, S Samuel; Wang, Xiaoyan; Palchevskiy, Vyacheslav et al. (2018) Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft. Transplantation 102:986-993
Gregson, A L; Wang, X; Injean, P et al. (2015) Staphylococcus via an interaction with the ELR+ CXC chemokine ENA-78 is associated with BOS. Am J Transplant 15:792-9
Gregson, Aric L; Hoji, Aki; Injean, Patil et al. (2015) Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection. Am J Respir Crit Care Med 192:1490-503
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Weigt, S S; Derhovanessian, A; Liao, E et al. (2012) CXCR3 chemokine ligands during respiratory viral infections predict lung allograft dysfunction. Am J Transplant 12:477-84
Huang, Hsuanwen C; Weigt, S Samuel; Derhovanessian, Ariss et al. (2011) Non-tuberculous mycobacterium infection after lung transplantation is associated with increased mortality. J Heart Lung Transplant 30:790-8
Weigt, S S; Elashoff, R M; Huang, C et al. (2009) Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant 9:1903-11