Doctoral Defense - Daniel Marri

About the Event

DEPARTMENT OF BIOMEDICAL ENGINEERING
Doctoral Dissertation Defense

May 14, 2024 | 1:00 PM
IQ Building Atrium and Zoom
Email Department or Advisor for Zoom information

Modeling the Spatio-Temporal Effect of 2,3,7,8 Tetrachlorodibenzo-p-dioxin on Hepatic Gene Expression

By: Daniel Marri

Advisor: Prof. Sudin Bhattacharya

Circadian clocks are intrinsic molecular oscillators present in cells across prokaryotes and eukaryotes that synchronize physiological processes with external cues, enabling organismal adaptation and survival. These clocks regulate crucial biological functions, including sleep-wake cycles, thermoregulation, hepatic metabolism, and hormonal secretion, through the rhythmic expression of clock-controlled genes. Perturbations in the circadian clock network can contribute to the pathogenesis of various disorders, such as obesity, diabetes, inflammatory conditions, and certain cancers. To understand the effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) on the spatial and temporal dynamics of the circadian clock genes, interpretable machine learning models were developed to predict BMAL1 binding to DNA in liver, kidney, and heart tissues using genetic and epigenetic features (binding sequence, DNA shape, and histone modifications). Furthermore, a spatiotemporal multicellular mathematical model of the mammalian circadian clock in the liver lobule was developed to investigate intercellular coupling for the synchronization of circadian clock expression across the portal-to-central axis. Lastly, to understand the interplay between the spatial and temporal axes of gene expression in the liver, particularly in drug metabolism pathways, non-linear mixed effect models were developed to analyze the acute effect of TCDD on the spatial temporal expression of genes in the hepatic lobule.
These findings provide a comprehensive examination of circadian rhythms and their disruption by TCDD in the liver, encompassing molecular mechanisms, predictive modeling, and spatiotemporal dynamics. Also, the study offers valuable insights into the intricate regulatory mechanisms governing circadian rhythms, the significance of zonation in hepatic functions, and the interplay between spatial and temporal gene expression. Taken together, our findings have the potential to contribute significantly to our understanding of circadian resilience and the mitigation of pathological conditions, particularly in the context of drug metabolism pathways and hepatic function.

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