vuga, louis J
(2016)
POTENTIAL DIAGNOSTIC AND PROGNOSTIC BIOMARKERS OF IDIOPATHIC PULMONARY FIBROSIS AND THE IMPACT OF E2F8 IN COLLAGEN 1 SYNTHESIS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Idiopathic pulmonary Fibrosis (IPF) is a chronic lung disease with median survival about 2-3.5 years (1). Lung transplant is the most effective therapy although pirfenidone (2) and nintetanib (3) delay mortality or disease progression. Biomarkers are used for diagnosis and management of diseases (4) but for IPF, a reliable biomarker is not established (5, 6). In this project, we proposed to investigate lung transcript expressions and plasma proteins as diagnostic or prognostic biomarkers and their implication in Pathogenesis of IPF.
First, we found 44 transcripts qualified after t-test, Benjamini and Hochberg multiple correction, and 1.5-fold change cutoff. We observed 33 transcripts that commonly distinguished IPF from control or COPD. The scoring coefficients of the principal components (COMP) distinguished IPF from control or COPD by using Classification Tree model. The receiver operating characteristic (ROC) curves for scoring coefficients of COMP of IPF vs control was with Area Under Curve (AUC) = 0.90 (95% CI), sensitivity 85% and specificity 91% and IPF or COPD was AUC= 0.88 (95% CI), sensitivity 86 % and specificity 90%.
Second, we measured 24 biomarkers in IPF plasma using Searchlight Protein Array. In cross-sectional study, intercellular adhesion molecule 1 (ICAM), vascular cell adhesion molecule 1 (VCAM1), and S100 calcium binding protein A12 (S100A12), and surfactant protein D (SFTPD) were predictors of IPF mortality (P < 0.05). In serial studies, previously identified proteins ICAM1, VCAM1, S100A12, interleukin 8 (IL8) and novel proteins matrix metallopeptidase 10 (MMP10) and tissue inhibitor of metalloproteinase 1 (TIMP1) were predictors of IPF mortality.
Third, we discovered in lung fibroblasts from IPF a deficiency of E2F transcription factor 8 (E2F8), which is eliminated by an F-box protein 16 (FBXO16). Biologically, E2F8 reduces fibroblast proliferation, and E2F8 also decreases collagen 1A1 mRNA synthesis. Hence, we found a model of lung fibrosis focusing on two novel molecular inputs (E2F8 and FBXO16) linked to fibroblast behavior in subjects with IPF.
In summary, our transcriptomic and plasma proteins analyses revealed the utility of biomarker discovery in advancing precision medicine in IPF. Together these finding provide novel insights that may improve IPF diagnosis, prognostic and potential drug discovery.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 September 2016 |
| Date Type: |
Publication |
| Defense Date: |
7 June 2016 |
| Approval Date: |
14 September 2016 |
| Submission Date: |
14 September 2016 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
92 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Clinical and Translational Science |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
IPF, Biomarkers, E2F8, Fibroblasts, Transcripts, lung |
| Date Deposited: |
14 Sep 2016 14:20 |
| Last Modified: |
15 Nov 2016 14:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/29520 |
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