BIOMED PhD Thesis Defense

Title: 
Transcriptomic Analysis of Circadian Rhythm Disruption and Intercellular Desynchrony in the Human Brain with Alzheimer's Disease

Speaker:
Henry Hollis, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisors:
Ron Anafi, MD, PhD
Associate Professor
Perelman School of Medicine
University of Pennsylvania

Andres Kriete, PhD
Associate Dean for Academic Affairs and Teaching Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University 

Details:
Disrupted behavioral circadian rhythms are a hallmark of Alzheimer’s disease (AD), but transcriptional rhythms in AD subjects have not been well studied. To address this, we informatically ordered post-mortem human brains with and without AD to reconstruct molecular rhythms in control (CTL) and AD samples. We found that while core clock rhythms remained largely intact, critical metabolic output pathways, specifically ribosome and oxidative phosphorylation, were severely dampened. 

Our experimental validation in mice mirrored these transcriptomic findings. A fundamental ambiguity in circadian biology is whether this type of tissue-level dampening stems from a loss of individual cellular amplitude or an increase in intercellular phase dispersion (cells drifting out of sync). To resolve this, we developed a novel computational framework: ORPHEUS. Applying this tool revealed that phase dispersion, rather than strictly weakened individual cellular rhythms, drives the dampened metabolic rhythms observed in AD. Ultimately, this work provides a detailed understanding of circadian disruption in neurodegeneration and introduces a powerful computational tool for analyzing complex tissue rhythms.

The School of Biomedical Engineering, Science and Health Systems is pleased to announce its 8th Annual Immune Modulation & Engineering Symposium (IMES).