Bokai Zhu, PhD, assistant professor of medicine at the Aging Institute and University of Pittsburgh, recently received a prestigious Maximizing Investigators’ Research Award (MIRA, R35) from the National Institute of General Medical Sciences (NIGMS). This multi-year award will support Dr. Zhu’s pioneering research on how cells maintain the health of their proteins over time — a process known as proteostasis — and how its failure contributes to aging and neurodegenerative disease.

Proteins constantly fold, refold, and degrade in every cell, forming the foundation of nearly all biological functions. Yet this delicate balance is continuously challenged by stress, environmental change, and the passage of time. “When proteostasis falters, proteins misfold and aggregate, driving many age-related disorders,” said Zhu. “Our goal is to uncover the fundamental principles that allow cells to anticipate and manage proteostatic stress before damage occurs.”

Over the past several years, Zhu’s team has uncovered an unexpected temporal pattern in this process. Rather than operating at a steady pace, many proteostasis genes follow a 12-hour rhythm, distinct from the 24-hour circadian clock. This “12-hour proteostasis oscillator” coordinates bursts of protein quality control activity around dawn and dusk — times when cells experience natural metabolic and oxidative stress.

The new MIRA grant will enable Zhu’s lab to address key unanswered questions:

• How do cells sense proteostatic stress before it becomes harmful?
• What molecular switches link stress sensing to rhythmic gene expression?
• How do structures inside the nucleus, known as nuclear speckles, act as command centers to orchestrate global proteostasis responses?

By combining advanced imaging, biophysical modeling, and genomics, the Zhu Lab will map how nuclear speckles change shape and composition in real time to activate protective genes. This work could reveal how these “nuclear control hubs” help cells preempt protein damage — and why their breakdown with age leads to degenerative disease.

The research also holds translational promise. Understanding how nuclear speckles regulate proteostasis could open entirely new therapeutic avenues for diseases driven by protein misfolding, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

“Proteostasis is life’s quality-control system,” said Zhu. “If we can learn how cells time and tune this process, we may find new ways to slow aging and prevent neurodegeneration.”

The Aging Institute celebrates this recognition of Dr. Zhu’s innovative science — and looks forward to seeing how his work reshapes our understanding of time, stress, and cellular resilience.