Doctoral Dissertations

Date of Award

12-2024

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Tian Hong

Committee Members

Maitreyi Das, Hong Guo, Tarek Hewezi

Abstract

Gene, protein and their regulators govern cellular and organismal responses to internal and external signals, coordinating essential processes that drive growth, differentiation, and adaptation. By mapping interactions among genes, regulatory networks provide a structured framework to simplify complex biological systems, enabling the analysis and prediction of cellular behaviors across diverse domains, revealing potential underlying principles common across different systems. This thesis employs regulatory network models to investigate fundamental mechanisms in three biological contexts. Although the core genes and molecules differ across each biological system, they are simplified to ‘nodes’ and ‘interactions among nodes’ within the regulatory network, whose dynamics can be calculated through differential equations. These node dynamics, linked to real biological insights and experimental approaches, reveal hidden mechanisms beyond what is directly observable. In the shoot apical meristem (SAM) project (Chapter II), we developed a mathematical model to examine the regulatory network controlling stem cell populations, focusing on the interaction between WUSCHEL (WUS) and CLAVATA3 (CLV3), with modulation by Epidermal Patterning Factor-Like (EPFL) proteins. The model reveals that EPFL and HAIRY MERISTEM signals synergize to stabilize WUS expression under perturbations, providing insight into the SAM's apical-basal and lateral axis patterning. In fission yeast project (Chapter III), we investigated Cdc42-mediated polarized growth, showing how alternating positive and negative feedbacks regulate growth cycles. Through experimental and modeling approaches, we found that endocytosis-dependent removal of Pak1 kinase is essential for Cdc42 reactivation, revealing a novel feedback mechanism involving branched actin-mediated endocytosis in the maintenance of cell polarity. In small cell lung cancer (SCLC) project (Chapter IV), we used an ordinary differential equation framework to model the dynamics among key subtypes defined by ASCL1, NEUROD1, and YAP1. Our model captures subtype-specific expression patterns and predicts stable intermediate states, consistent with transcriptome data. This work provides a map of SCLC subtype dynamics, offering insights into the mechanisms driving tumor heterogeneity and progression. Together, these studies highlight the utility of regulatory networks and dynamic modeling help to understand phenomena in complex biological systems.

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