- Title Information
- Title
- A Multiomics Approach to Evaluate Advances in Liver Transplantation
- Type of Resource (primo)
- dissertations
- Name:
Personal
- Name Part
- Ohman, Anders William
- Role
- Role Term:
Text
- creator
- Name:
Personal
- Name Part
- Sanders, Jennifer
- Role
- Role Term:
Text
- Advisor
- Name:
Personal
- Name Part
- Tapinos, Nikos
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Reichner, Jonathan
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Freiman, Richard
- Role
- Role Term:
Text
- Reader
- Name:
Personal
- Name Part
- Uygun, Korkut
- Role
- Role Term:
Text
- Reader
- Name:
Corporate
- Name Part
- Brown University. Biology and Medicine: Pathobiology
- Role
- Role Term:
Text
- sponsor
- Origin Information
- Copyright Date
- 2023
- Physical Description
- Extent
- xvii, 183 p.
- digitalOrigin
- born digital
- Note:
thesis
- Thesis (Ph. D.)--Brown University, 2023
- Genre (aat)
- theses
- Abstract
- Liver transplantation remains the standard of care for liver failure but is constrained by a shortage of organs. Fetal hepatic cell transplantation (HCT) offers a potential therapeutic alternative as fetal hepatocytes persist and proliferate in animal models and human clinical trials, however they cannot be readily procured for clinical use. Normothermic machine perfusion (NMP) may better preserve donor organs than hypothermic storage and even rehabilitate marginal grafts with or without the addition of adjuvants in the perfusion solution, but it is not commonly employed in the clinic. For both HCT and NMP, it is critical to develop a mechanistic understanding of these techniques’ effects on cell biology using multiomics. Pre- and post-HCT fetal and adult rat liver were collected using laser capture microdissection or immunopurification. Human donor livers rejected for transplantation were analyzed for functional metrics and biopsied before and during NMP. Epigenomic histone post-translational modification (hPTM) profiles and the perfusate proteome were quantified by mass spectrometry, and the transcriptome was quantified by next-gen mRNA sequencing. Fetal colonies retained a distinct subset of hPTM abundance and mRNA expression patterns in common with pre-transplant cells. These retained differences may drive the competitive growth advantage seen in fetal cells post-transplant and could potentially be harnessed to improve HCT outcomes. Significant hPTMs were all on Histone H3 and have known associations with gene transcription activity, and the colony DEGs reflect enrichment of biological processes associated with ion transport. Following NMP, we found approximately half of the perfused discarded human livers met functional criteria for transplantation. These livers expressed a significantly different pattern of gene expression at both 3 and 6 hours of perfusion, with functional livers expressing suppressed apoptosis and activated autophagy. A follow-up study applying caspase inhibition during NMP resulted in treated livers more closely resembling adequately functional donor livers than inadequately functional ones, and reduced expression of apoptosis biomarkers. Both studies inform potential pharmacological interventions to improve these techniques.
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01000617")
- Topic
- Liver
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01079714")
- Topic
- Proteins--Analysis
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00957680")
- Topic
- Histones
- Subject
- Topic
- multi-omic data
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01000691")
- Topic
- Liver--Transplantation
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/00923393")
- Topic
- Fetal liver cells--Transplantation
- Subject (fast)
(authorityURI="http://id.worldcat.org/fast", valueURI="http://id.worldcat.org/fast/01017395")
- Topic
- Messenger RNA--Analysis
- Language
- Language Term (ISO639-2B)
- English
- Record Information
- Record Content Source (marcorg)
- RPB
- Record Creation Date
(encoding="iso8601")
- 20230207
- Identifier:
DOI
- 10.26300/6ca2-b727