Gregg, Robert
(2020)
Multi-Scale Modeling of the Innate Immune System: A Dynamic Investigation into Pathogenic Detection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Having a well-functioning immune system can mean the difference between a mild ailment and a life-threatening infection; however, predicting how a disease will progress has proven to be a significant challenge. The dynamics driving the immune system are governed by a complex web of cell types, signaling proteins, and regulatory genes that have to strike a balance between disease elimination and rampant inflammation. An insufficient immune response will induce a prolonged disease state, but an excessive response will cause unnecessary cell dead and extensive tissue damage. This balance is usually self-regulated, but medical intervention is often necessary to correct imbalances. Unfortunately, these therapies are imperfect and accompanied by mild to debilitating side-effects caused by off-target effects. By developing a detailed understanding of the immune response, the goal of this dissertation is to predict how the immune system will respond to infection and determine how new potential therapies could overcome these threats.
Computational modeling provides an opportunity to synthesize current immunological observations and predict response outcomes to pathogenic infections. When coupled with experimental data, these models can simulate signaling pathway dynamics that drive the immune response, incorporate regulatory feedback mechanisms, and model inherent biological noise. Taken together, computational modeling can explain emergent behavior that cannot be determined from experiment alone. This dissertation will unitize two computational modeling techniques: ordinary differential equations (ODEs) and agent-based modeling (ABMs). Ultimately, they are combined in a novel way to model cellular immune responses across multiple length scales, creating a more accurate representation of the pathogenic response.
TLR4 and cGAS signaling are prominent in a number of diseases and dysregulations including---but not limited to---autoimmunity, cancer, HIV, HSV, tuberculosis, and sepsis. These two signaling pathways are so prevalent because they are activated extremely early and help drive the downstream immune signaling. Modeling how cells dynamically regulate these pathways is critical for understanding how diseases circumvent feedback mechanisms and how new therapies can restore immune function to combat disease progression. By using ODE and ABM techniques, these studies aim to incrementally expand our knowledge of innate immune signaling and understand how feedback mechanisms control disease severity.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
28 September 2020 |
| Date Type: |
Publication |
| Defense Date: |
20 July 2020 |
| Approval Date: |
28 September 2020 |
| Submission Date: |
24 July 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
134 |
| 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: |
cGAS, Sepsis, Interferon, Agent-Based Model |
| Date Deposited: |
28 Sep 2020 18:43 |
| Last Modified: |
28 Sep 2020 18:43 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39379 |
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