Kai Zhou, PhD, Buck Fellow

Description of research

 Aging is a general physiological deterioration that constitutes the primary risk factor for major human pathologies, including cancer, cardiovascular, metabolic, autoinflammatory and neurodegenerative diseases. Research to develop cures for these diseases has been hampered because we lack a clear understanding of the factors that underlie the aging contribution. Elucidating these factors remains an important frontier in aging research and will accelerate our ability to intervene in aging-related diseases. Dr. Kai Zhou and his lab study mechanisms underlying the cellular aging process with a particular emphasis on the protein homeostasis (proteostasis). Proteostasis, maintained through gating both protein folding and misfolding, is the key for biological systems to live long and prosper as almost all cellular functions are fulfilled by specific proteins. Proteins in a cell are metastable and not only threatened by the crowded cellular environment, but also affected by mutations, mistakes in translation and post-translational modifications, as well as unpredictable environmental stresses. Proteins tend to misfold with age, which impairs the proteostasis and is believed to be the underlying cause for many age-related diseases including Alzheimer’s and Parkinson’s. The Zhou lab will study protein folding and misfolding in both young and aging cells – with the goal of understanding the events that lead to the loss of proteostasis during cellular aging and disease as well as identifying mechanisms that can be exploited to rejuvenate aging cells.

The Machinery of Life by David S. Goodsell

Fig1.The Machinery of Life by David S. Goodsell

Life On The Edge of Misfolding:
To ensure protein folding, the cells have evolved a sophisticated and efficient protein quality control system, such as molecular chaperones, ubiquitin-proteasome, autophagy, etc., to maintain the balance between expression, folding, modification, and degradation of each protein to ensure proper protein-protein interaction, and consequently the organization of macromolecules within a cell. This protein quality control system was “designed” with the philosophy of sacrificing energy efficiency for information accuracy. For example, in addition to the damaged proteins, the quality control system discards a significant portion of newly synthesized polypeptides. More than that, this system is able to patrol through the crowded cytosol or organellar matrix with >340mg/mL proteins (Fig1) to efficiently identify and remove the unwanted proteins. When the efficiency of this security system fails to cope with the occurrence of impaired proteins, the cytosol will be jammed with these damaged polypeptides that cause a broad spectrum of cellular dysfunction, which chronically leads to aging and age-related diseases. Our lab is interested in understanding how the young cells are able to maintain proteostasis and what are missing during aging that prevent old cells from efficiently disposing damaged proteins? We are using genetics, biophysics, biochemistry, imaging, proteomics and bioinformatics to understand the protein folding and misfolding mechanisms in both young and old cells, which will guide us to design strategies to restore proteostasis in old cells.

Cell Biology of Aging:
Although it is well accepted that the failure of protein quality control will lead to cellular dysfunctions and chronically cause cellular aging, however, we have limited knowledge regarding which cellular processes are affected and how the old cell, which accumulate damaged proteins, can manage to survive the chronic proteostasis crisis for almost half of its life span. In addition to that, the asymmetric segregation of age between sibling cells allows one of them to restore proteostasis through unknown mechanisms. We use the budding yeast Saccharomyces cerevisiae to study these topics systematically and comprehensively in molecular and cellular levels. Budding yeast has been proven to be a great model system for research on cellular aging. By leveraging the unlimited genetic tools and libraries, one can progress quickly on projects to provide insights for the fundamental biology questions. We are also developing new methodologies and platforms to broaden our technology portfolio that can be unleashed to break through current limitations in the field and stride our understanding of aging and age-related diseases.

Dr. Zhou is a recipient of the NIH Director's Early Independence Award, which is a part of the National Institutes of Health’s (NIH) High-Risk, High-Reward Research program that funded 86 awards to exceptionally creative scientists proposing to use highly innovative approaches to tackle major challenges in biomedical research.

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Recent Publications

2017

Linhao Ruan, Chuankai Zhou... Rong Li "Cytosolic proteostasis through importing of misfolded proteins into mitochondria." Nature 543:7645 443-446

2014

Chuankai Zhou, Rong Li... Brian K Kennedy "Life history: mother-specific proteins that promote aging." Curr. Biol. 24:24 R1162-4
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