Surrogate Biomarkers in Chronic Lung Graft Rejection

Newark Beth Israel Medical Center, Newark NJ

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Abstract

DESCRIPTION (provided by applicant): The primary goal of this proposal is to provide a framework for my scientific development and facilitate my transition to becoming an independent investigator. The Clinical Research Training Program (CRTP) and the Lung Translational Genomics Center at the University of Pittsburgh combine to provide me with the ideal environment to obtain and apply the necessary skills for the study of novel surrogate blood biomarkers in chronic lung allograft rejection (OB/OS). OB/BOS is the main impediment to long-term survival in lung transplant recipients (LTRs) and its etiology and pathogenesis are largely unknown. Currently, OB/BOS diagnosis requires either a lung biopsy, which is invasive, costly and of limited sensitivity, or a decline in spirometric lung function, which represents irreversible loss of greater than 20% of lung function. The central hypothesis of this proposal is that airway remodeling, which characterizes OB/BOS, requires a shift in the inflammatory environment from a predominantly IFN-gamma response (antifibrotic milieu) to a profibrotic response characterized by induction of cytokines such as TGF-beta. Targeted secreted protein and global gene expression profiles in the peripheral blood of LTRs will demonstrate this shift allowing identification of combinatorial biomarkers that will be indicative of risk, progression and outcome of OB/BOS. Sequential, paired peripheral blood and bronchoalveolar lavage specimens will be obtained from 100 lung transplant recipients, which will then be studied via the following specific aims: (1) Identify changes in plasma profibrotic cytokines and growth factors in LTRs that predict the development of OB/BOS;(2) Identify temporal changes in gene expression profiles in peripheral blood mononuclear cells (PBMC) that are predictive of favorable long-term response versus those predictive of subsequently developing OB/BOS;While Aim 1 investigates a shift in circulating proteins, Aim 2 evaluates the genes induced in blood cells by this antifibrotic to profibrotic cytokine shift. (3) Determine gene expression and targeted secreted protein patterns in bronchoalveolar lavage fluid (BAL) to identify lung OB/BOS biomarkers that may coincide with those surrogates observed in blood or provide a graft-localized biomarker signal. Through regular interaction with the senior faculty of the CRTP and the experienced investigators who comprise my mentorship committee, I anticipate building the necessary foundation for a successful independent academic career. (End of Abstract)