Dissertation
Insights into the mechanisms underlying calpain-related pathology
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2020
DOI: 10.17077/etd.005662
Abstract
The molecular interactions underlying vitreoretinopathy are poorly understood. Mutations in calpain-5 (CAPN5) were identified as the cause of autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). CAPN5 is a member of the calcium-activated cysteine protease family referred to as calpains, which modulate the function of their targets through limited proteolysis. Although increases in calpain activity are associated with many different diseases, ADNIV-causing mutations in CAPN5 are the first reported intrinsically hyperactive case of a calpain. Although ADNIV is relatively rare, it shares overlapping phenotypes with multiple, more common ocular diseases, including diabetic retinopathy. This provides an unprecedented starting point for investigating the substantial gap in our understanding of the molecular basis of vitreoretinopathy. In this thesis, the expression patterns of CAPN5 in the eye and brain are reported (Chapters 2 and 3). I discuss the identification and validation of a CAPN5 substrate and its role in ADNIV. This association is extended as an underlying mechanism in diabetic retinopathy. Utilizing this information, I identify the proteolysis site and alter it to create the first CAPN5-specific and ADNIV-causing-mutation specific inhibitors (Chapter 4). Insights gained from these studies may be used to design therapies for ADNIV, diabetic retinopathy, and other calpain-associated pathologies. Lastly, in an attempt to better understand how increased calpain activity contributes to a myriad of diseases, we created a mouse model in which we express a synthetic hyperactive calpain protein (Chapter 5).
Details
- Title: Subtitle
- Insights into the mechanisms underlying calpain-related pathology
- Creators
- Kellie Ann Schaefer
- Contributors
- Vinit Mahajan (Advisor)Alexander Bassuk (Advisor)Polly Ferguson (Committee Member)Robert Cornell (Committee Member)Benjamin Darbro (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Autumn 2020
- DOI
- 10.17077/etd.005662
- Publisher
- University of Iowa
- Number of pages
- xv, 148 pages
- Copyright
- Copyright 2020 Kellie Ann Schaefer
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 135-148).
- Public Abstract (ETD)
Blindness is one of the biggest fears faced by individuals. Although this can occur many ways, one blinding disease is on the rise throughout the world, diabetic retinopathy (DR). It is estimated over 10% of Americans are living with diabetes. At least a third of those patients over the age of forty have DR. This number is expected to increase dramatically in the near future. Current treatments for DR are limited.
Another eye disease, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), shares some features of DR. ADNIV is caused by mutations in the CAPN5 gene, which encodes for a protease. Proteases alter other proteins and their functions by cutting them. It is believed the mutations in CAPN5 cause disease by increasing the activity of CAPN5 resulting in uncontrolled cutting.
To understand how CAPN5 mutations lead to disease, and how this disease overlaps with the more common diabetic retinopathy, I conducted studies which focus on where CAPN5 is expressed in the eye and brain. Next, I determined CAPN5 alters the blood vessel-forming platelet-derived growth factor B (PDGFB) protein, which has been extensively implicated in DR. Furthermore, I located where CAPN5 cuts PDGFB and altered this cut site to disrupt further cutting by CAPN5. This approach, as well as the inhibitor I designed, could be used to develop new treatments for both ADNIV and DR patients.
- Academic Unit
- Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984035989702771
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