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 molecular biomarkers in chronic lung allograft rejection (OB). OB is the main impediment to long-term survival in lung transplant recipients (LTRs), and its etiology and pathogenesis are largely unknown. Currently, OB diagnosis requires either a lung biopsy, which is invasive, costly and of limited sensitivity, or a decline in spirometric lung function, which represents the irreversible loss of greater than 20% of lung function. The central hypothesis of this proposal is that the systemic inflammatory environment of OB, detected by gene expression patterns in peripheral blood mononuclear cells (PBMC) and serum cytokine profiles of LTRs, is reflective and predictive of the development of OB. These inflammatory changes often precede the development of irreversible tissue injury and are therefore amenable to targeted identification of highly accessible and accurate biomarkers of OB. This may facilitate understanding of mechanisms underlying this devastating disease.
Specific aims to address this hypothesis include: (1) Generate a prospective collection of sequential serum and PBMC samples from a cohort of 100 carefully characterized and prospectively followed LTRs (2) study gene expression profiles in PBMC to identify specific markers of OB.
This aim will also include time coursed analysis of gene expression profiles in PBMC to identify ongoing expression profiles and temporal changes that are predictive of favorable long-term response versus developing OB. (3) Identify combinatorial changes in serum expression of secreted inflammatory cytokines that predict OB. Multiplex cytokine assays will be used. 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 academic career.
|Studer, Sean M; George, M Patricia; Zhu, Xuehai et al. (2008) CD28 down-regulation on CD4 T cells is a marker for graft dysfunction in lung transplant recipients. Am J Respir Crit Care Med 178:765-73|