Date of Award

Summer 6-10-2024

Embargo Period

6-10-2029

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

Additional Department

Medicine

College

College of Graduate Studies

Additional College

College of Medicine

First Advisor

Carol Feghali-Bostwick

Second Advisor

Amy Bradshaw

Third Advisor

Andrew Goodwin

Fourth Advisor

Patrick Flume

Fifth Advisor

Donald Menick

Sixth Advisor

Henry Sucov

Abstract

Problem Statement:

Pulmonary fibrosis (PF) is a clinically severe and commonly fatal complication of Systemic Sclerosis (SSc). Our group has previously reported profibrotic roles for Insulin-like Growth Factor II (IGF-II) and Lysyl Oxidase (LOX) in SSc-PF.

Approach, Materials, Methods:

We sought to identify downstream regulatory mediators related to IGF-II signaling. In the present work, we show that SSc lung tissues have higher baseline levels of the total (N-glycosylated/unglycosylated) LOX-Propeptide (LOX-PP) than normal lung tissues.

Major Findings:

LOX-PP mediated changes which were consistent with the extracellular matrix (ECM) deregulation implicated in SSc-PF progression. Furthermore, Tolloid-like 1 (TLL1) and Bone Morphogenetic Protein 1 (BMP1), enzymes that can cleave ProLOX to release LOX-PP were increased in SSc lung fibrosis and the bleomycin (BLM)-induced murine lung fibrosis model, respectively. In addition, IGF-II regulated the levels of ProLOX, active LOX, LOX-PP, as well as BMP1 and isoforms of TLL1. The Class E Basic Helix-Loop-Helix protein 40 (BHLHE40) transcription factor localizes to the nucleus in response to IGF-II. BHLHE40 silencing downregulated TLL1 isoforms and LOX-PP and restored significant features of ECM deregulation triggered by IGF-II.

Conclusion:

Our findings indicate that IGF-II, BHLHE40 and LOX-PP may serve as targets of therapeutic intervention to halt SSc-PF progression.

Rights

Copyright is held by the author. All rights reserved.

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