Ackerman, Emily E.
(2021)
Controls Engineering Approaches To Regulating Immunity During Respiratory Infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The human immune system is responsible for the detection and elimination of pathogens. The immune response to viral infection is comprised of a complex set of multi-scale interactions between small molecules, proteins, genes, and cells that govern pro-inflammatory and anti-inflammatory processes. Overactive inflammation is a root cause of severe clinical outcomes and can lead to systemic tissue damage and death. Identifying the drivers of dysregulation is key in the development and administration of therapeutic treatments to maintain equilibrium. The work presented aims to utilize high throughput and immunological data to determine the causal agents of immunoregulation using systems biology tools. Developed methods address this problem at the protein and systems levels using protein-protein interaction (PPI) network methods and ordinary differential equation (ODE) models.
Aim 1, the creation of the first ever disease specific subnetwork, identifies a set of proteins that are enriched for possible antiviral drug targets for influenza A infection. In Aim 2, PPI network controllability analyses are used to identify a set of 24 and 16 proteins acting as regulators of influenza A and SARS-CoV-2 infection, respectively. These proteins are further prioritized as targets in drug development/repurposing based on topology, function, and known targeting compounds. Five previously unidentified compounds are recommended for repurposing to treat COVID-19. Together, Aims 1 and 2 computationally produce efficient and meaningful biological results which align with in vivo findings.
Aim 3 explores influenza A strain-specific dynamics observed in immunological data by using ODE models to elucidate which biological mechanisms are at the root of differential behavior. Two models are constructed and parameterized to explore H1N1 and H5N1 influenza dynamics. Study reveals that only a small number of host functions likely contribute to the strain-specific response, particularly the production rate of interferon. This finding is informative to future exploration of interferon-based therapeutics.
In total, both approaches are useful in teasing out the drivers of emergent properties of the complex immune response. By determining the consequences of the presence of a single component like interferon on other immune mechanisms, these studies enhance our understanding of disease progression and open the door to knowledgeable treatment design.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Ackerman, Emily E. | | | |
|
| ETD Committee: |
|
| Date: |
3 September 2021 |
| Date Type: |
Publication |
| Defense Date: |
16 July 2021 |
| Approval Date: |
3 September 2021 |
| Submission Date: |
2 July 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
166 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Chemical and Petroleum Engineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
hail-to-pitt, pittetd, theses, format |
| Date Deposited: |
03 Sep 2021 16:12 |
| Last Modified: |
03 Sep 2021 16:12 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41384 |
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