Lefever, Daniel E.
(2023)
An application of Quantitative Systems Pharmacology to Repurpose Drugs for Non-Alcoholic Fatty Liver Disease.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Biological research, like most other fields of research and technology, has experienced an exponential growth in productivity since the 1950’s. However, drug discovery as one of the main practical applications of biological research has become exponentially more expensive and the efficiency of success remains low. Among the most important reasons for this low efficiency is that several major unmet medical needs involve diseases that are complex and heterogeneous, presenting challenges for traditional drug discovery approaches. Non-alcoholic fatty liver disease (NAFLD) is one such disease in which despite billions being spent, the approaches used by current drug discovery efforts has not yielded any Food and Drug Administration (FDA) approved drugs in the US. NAFLD is a disease driven by multiple independent pathways and molecular targets which may not be amenable to single targeted therapeutics. This dissertation demonstrates how a relatively new approach to drug discovery, Quantitative Systems Pharmacology (QSP), can be used to discover drugs for NAFLD by predicting existing drugs for repurposing and by identifying disease networks comprising potential molecular targets for novel drug discovery.
Chapter 1 gives an overview of NAFLD and the rationale for using QSP. Chapter 2 describes results using patient transcriptome data to comprehensively and unbiasedly define disease states that promote NAFLD progression. In Chapter 3, the Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 database was used to predict drugs able to normalize these disease states and were then experimentally tested in a human liver acinus microphysiology system (LAMPS) of NAFLD. A proof-of-concept study in LAMPS demonstrated mitigation of steatosis, inflammation, and fibrosis especially with drug combinations. Chapter 4 further establishes the clinical relevancy of LAMPS as a model of NAFLD. Currently, experimental testing of more predicted compounds is being performed. In conjunction with iPSC-derived cells, this approach has the potential for developing personalized NAFLD therapeutic strategies, informing disease mechanisms, and defining optimal cohorts of patients for clinical trials.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
15 September 2023 |
| Date Type: |
Publication |
| Defense Date: |
6 January 2023 |
| Approval Date: |
15 September 2023 |
| Submission Date: |
9 March 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
135 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Integrative Systems Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
liver; non-alcoholic fatty liver disease; NAFLD; Metabolic-associated fatty liver disease; MAFLD; microphysiology systems; MPS; drug discovery; quantitative systems pharmacology; QSP; connectivity map; CMap; drug repurposing; network proximity; non-alcoholic steatohepatitis; NASH; fibrosis; lobular inflammation; steatosis; targeting disease states; drug combinations; |
| Related URLs: |
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| Date Deposited: |
15 Sep 2023 15:44 |
| Last Modified: |
15 Sep 2023 15:44 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44268 |
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