Dissertation
Studying complement regulation in a C3 glomerulopathy-specific microenvironment
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.006822
Abstract
The complement system is a cornerstone of the innate immune response: it facilitates pathogen identification and clearance via the self-amplification cascade, while being tightly controlled on host surfaces to prevent tissue damage. C3 glomerulopathy (C3G) is a group of ultra-rare complement-mediated renal diseases. The underlying cause of C3G pathogenesis stems from inadequate control of the alternative pathway (AP) of complement on the surface of glomerular basement membrane (GBM), causing C3 deposition within the GBM. The resulting kidney damage leads to about 50% of C3G patients progressing to end-stage renal disease within 10 years of diagnosis.
C3G is a multifactorial disease driven in most patients by autoantibodies against complement proteins and complexes (acquired drivers), and/or pathogenic variation in complement genes (genetic drivers), however, a subset of C3G patients have no identified complement-related drivers of disease. Such heterogeneity of presentations poses a challenge when investigating molecular mechanisms of this disease. This thesis will describe several studies performed with the goal of improving our understanding of C3G pathogenesis within the glomerular microenvironment. Here we present a novel in vitro model of AP activation on human extracellular matrix (ECM) surface, which allowed us to discover a new mechanism wherein autoantibodies against AP C3 convertase mediate C3G pathogenesis, and provided us with a platform to study the effects of ECM remodeling on complement regulation. Taken together, our findings provide insight into our basic understanding of the interplay between the components of complement system and the different microenvironments they act upon, furthering our ability to uncover the unknown drivers of C3G and improve patient outcomes.
Details
- Title: Subtitle
- Studying complement regulation in a C3 glomerulopathy-specific microenvironment
- Creators
- Sofiya Pisarenka
- Contributors
- Richard Smith (Advisor)Rory Fisher (Committee Member)Paul McCray (Committee Member)Robert Mullins (Committee Member)Carla Nester (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.006822
- Publisher
- University of Iowa
- Number of pages
- xv, 101 pages
- Copyright
- Copyright 2023 Sofiya Pisarenka
- Language
- English
- Date submitted
- 04/22/2023
- Date approved
- 06/30/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 91-101).
- Public Abstract (ETD)
- The innate immune system is our first line of defense against invading pathogens. The complement system is a major contributor to innate immunity. It consists of over 30 different proteins that help identify and remove harmful and unwanted materials present in the body, as well as initiate larger immune responses. The complement system is tightly controlled by many different mechanisms to ensure that it can only be activated when an immune response is needed. If those control mechanisms fail, the complement system becomes overactivated and can cause damage to our own organs. C3 glomerulopathy (C3G) is a kidney disease that is caused by complement overactivation, and the focus of this thesis work. C3G is an extremely devastating disease – about 50% of all C3G patients reach kidney failure within 10 years of diagnosis. Currently, we do not have a disease-specific treatment for C3G, and the treatments in use only help to manage the symptoms. The main goal of studies presented in this thesis was to better understand how exactly complement overactivation in the kidney environment leads to development of C3G at the molecular level. During the course of these studies, we discovered a new mechanism through which other parts of the immune system influence complement and lead to its overactivation. These findings are important to help guide future C3G research and identify new targets for therapeutic intervention.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984425314002771
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