Date of Award

January 2021

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Daniel Jane-wit

Abstract

Cardiac allograft vasculopathy (CAV) is a complex vaso-occlusive complication of heart transplantation currently identified as a major limiting factor to long-term survival in those who receive a cardiac transplant. In CAV, neointimal lesions form in graft vessels leading to ischemic complications and ultimately allograft loss. CAV is medically untreatable and affects ~50% of heart transplant patients. Endothelial cells (ECs) are a critical site where CAV lesions form, and antibodies produced by the recipient that bind to donor HLA molecules on graft endothelium (donor specific antibodies) have been identified as a key mediator in this process. Recent studies have further identified a role for antibody-mediated complement fixation, specifically in determining pro-inflammatory signaling changes induced through this process. The laboratory of my mentor, Dr. Jane-wit, studies complement-mediated signaling in ECs and has previously identified a signaling pathway implicated in CAV. In an unbiased assay to identify new components of this pathway, I unexpectedly found that TGF-ß signaling molecules, canonically understood to be anti-inflammatory, were involved in complement-induced EC activation. During my thesis I defined a novel function for proteasomes as cellular chaperones to activate TGF-ß signaling in response to complement activation. My thesis studies identify a pathologic role for endothelial TGF-ß signaling in CAV.

Comments

This is an Open Access Thesis.

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