Proteins in a cell are metastable and not only threatened by the crowded cellular environment, but also affected by mutations, mistakes in translation and posttranslational modifications, and unpredictable environmental stresses. Proteins tend to misfold with age, which impairs protein homeostasis and is believed to be an underlying cause for many age-related diseases, including Alzheimer’s and Parkinson’s. Protein homeostasis (proteostasis), maintained through balancing 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.
The Zhou lab studies mechanisms underlying the cellular aging process, with a particular emphasis on proteostasis. We 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. Our lab uses the budding yeast Saccharomyces cerevisiae to study these topics systematically and comprehensively at the molecular and cellular levels. Budding yeast has been proven to be a great model system for research on cellular aging and revealed longevity mechanisms that are highly conserved in metazoan. By leveraging genetic tools and libraries, we hope to progress quickly on projects to provide insights for fundamental biological 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 improve our understanding of aging and age-related diseases.
Why it matters
Aging is a general physiological deterioration that constitutes the primary risk factor for major human pathologies, including cancer, cardiovascular diseases, 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 process. Elucidating these factors remains an important frontier in aging research and will accelerate our ability to intervene in age-related disease. Recent setbacks in clinical trials for Alzheimer’s disease have sparked a new wave of basic research to understand protein folding and misfolding during aging and disease progression. Proteostasis is the basis for all cellular functions, and its mechanisms are highly conserved. Yeast has long served as a living test tube for proteostasis research and will continue to be a centerpiece of our further understanding of proteostasis in both healthy young individuals and older adults manifesting age-related diseases.
Proteins are the building blocks of life. My lab focuses on understanding age-related protein folding and disease-related misfolding as an essential component of efforts to intervene in age-related disease.
Kai Zhou, PhD
Dr. Zhou, the first Buck Fellow, joined the Institute directly after his thesis work. Dr. Zhou received his PhD in molecular and integrative physiology from the University of Kansas School of Medicine and the Stowers Institute for Medical Research.
Dr. Zhou has been awarded a prestigious $2.4 million Early Independence Award from the National Institutes of Health. As part of the NIH Director’s Award in the High-Risk, High-Reward Research program, this five-year grant allows Dr. Zhou to skip traditional postdoctoral training and move immediately into independent research.
Contact Dr. Zhou:
Catherine Chang Associate Scientist
Catherine Chang received her bachelor's degree in Biochemistry and Molecular Biology from UC Santa Cruz in 2016. As an undergraduate student, she investigated the effects of macromolecular crowding on protein folding. Catherine joined the Zhou Lab in August 2018 where she continues to pursue her research interest of protein folding and regulation. When away from the lab, you can expect to find Catherine enjoying the great outdoors!
Matt Domnauer PhD Candidate, Buck-USC Biology of Aging Program
Matt Domnauer is studying the biology of aging through a joint PhD program between the Buck Institute and the University of Southern California. He graduated from UC Santa Cruz in 2016 with a degree in Molecular, Cell, and Developmental biology where he studied the biochemical mechanisms regulating cell size and growth rate. Matt joined the Zhou lab in 2018 where he studies how cellular stress affects protein homeostasis in aging cells.
Benjamin Fong Research Intern
Benjamin Fong joined the Zhou lab in 2020 where he studies image analysis and develops analysis pipelines. He received his bachelor’s degree in applied and computational mathematics from San Jose State University in 2018. Ben is interested in pursuing a MS in bioinformatics.
Qingqing Liu, PhD Postdoctoral Research Fellow
Dr. Liu is from China and holds a bachelor’s degree in biological engineering. In 2017, she earned her PhD in microbiology and immunology at the China Agricultural University, where she worked on the circadian clock and the ubiquitin-proteasome system. Interested in protein homeostasis and aging, she joined the Zhou lab in February 2018. She is optimistic and believes that she will overcome all kinds of difficulties with her perseverance. In her spare time, she enjoys doing traditional Chinese needlework, which makes her relaxed and happy.
Wasti Nurani Research Scholar
During her PhD training at Technical University of Denmark, Wasti Nurani developed multiple strategies to improve the ability of Saccharomyces cerevisiae in metabolizing various non-sugar carbon sources, particularly ethanol, acetate, pyruvate, lactate, and glycerol. Among others, she discovered how modifications to proteostasis network components, including proteasome and chaperones, can substantially affect the metabolic capacity and vice versa. Believing that the molecular understanding of those mitochondria-involving phenomena could potentially be harnessed to modify aging and chronic diseases progression, Wasti joined the Zhou lab to study proteostasis in the context of mitochondrial physiology.
A. W.Alexandra Wooldredge Research Associate
Fan Zheng, PhD Postdoctoral Research Fellow
Dr. Zheng focused on studying microtubule dynamics regulation and mitochondrial dynamics regulation during her PhD training at the University of Hong Kong (HKU). She underwent her postdoctoral training and research experience as an associate investigator at the University of Science and Technology of China (USTC). Intrigued by the important roles of mitochondria in the context of aging and neurodegenerative diseases, Dr. Zheng joined the Zhou lab at Buck in 2019. Now she is studying the plasticity of mitochondrial proteome under stress conditions using the model organisms S.cerevesiae and Drosophila.
The Zhou lab has an opening for a Postdoctoral Researcher to study protein folding problems during stress and cellular aging in the Zhou lab. The Zhou lab uses budding yeast as the main model organism to research the principles of protein folding and how this process is affected by environmental stress and the aging process, as well as how the protein folding problems feedback to cellular aging. Budding yeast is an ideal model to study how mother cells age and how daughter cells reset their aging clock; both fates happen at the same time along the axis of asymmetric cell division.
We use multiple cutting-edge imaging methods, high-throughput screening, biochemistry, bioinformatics, and machine learning to systematically address the response of cellular proteome towards stress and aging. We also design and engineer new tools to solve the problems we face. As protein folding problems are featured and conserved in aging and many age-related diseases, including neurodegenerative diseases, our strategy is to take advantage of the high-throughput platforms in budding yeast and use the novel mechanisms revealed by yeast projects to guide further exploration in other animal models (e.g. fruit fly) for aging and age-related diseases. We follow basic questions and use unbiased screens to find answers and candidate proteins/genes, which are followed in detail to highlight the molecular mechanisms and gain insight into the principle of cell biology of proteostasis. The Postdoctoral Fellow is encouraged to finish 1-2 projects and publish high profile papers within 5 years and take the projects to his/her own lab in the future.
- Ph.D. or M.D. degree in biology or related fields
- Published research in peer-reviewed journals
- Interest in proteostasis and cell biology
- Previous research experience in cell biology or biochemistry is preferred
To apply, click here
Research Associate I
The Zhou lab has an opening for a Research Associate to study protein folding problems during cellular aging in the lab of Dr. Kai Zhou. The Zhou lab uses budding yeast to study the principles of protein folding and how aging affects this process, as well as how protein folding problems feed back to cellular aging. As protein folding problems are featured in aging and many age-related diseases, including neurodegenerative diseases, the mechanisms revealed with a basic cellular aging model will guide further exploration in other animal models for aging and age-related diseases.
Instead of just preparing medium and reagents, the Research Associate will be part of a collaborative project with other students/postdocs in the lab and responsible for driving the progress of his/her part of the project independently.
This project will be finished within a year and the RA will co-first author the resulting paper.
Education & Experience
- Bachelor’s degree in biology or related fields.
- Strong interest in learning new scientific techniques and working side-by-side with PI in the lab.
- Candidate will learn genetics, cell biology, proteomics, biochemistry, imaging and bioinformatics to solve the protein folding and aging–related questions.
- Rewarding and challenging experience for highly motivated individual.
- Ideal position for graduates seeking research experience and publications required for future graduate or medical school applications.
To apply: click here
- Domnauer, M., Zheng, F., Li L., Zhang, Y., Chang, C., Unruh J., Conkright-Fincham, J., McCroskey, S., Florens, L., Zhang, Y., Fong, B., Sharma, R., Ramanathan, A., Si, K.,*, and Zhou, C.*. Proteome plasticity in response to persistent environmental change. Molecular Cell. 2021 Aug 19;81(16):3294-3309.
- Liu, Q., Chang, C., Fong, B., Unruh, R., Guo, F., Si, K., Kennedy, K., Li, R., and Zhou, C*. Mitochondrial origin of cytosolic protein aggregation and proteostasis. Under revision. (*corresponding author) (Preprint available at SSRN: http://dx.doi.org/10.2139/ssrn.3808300)
- He, C., Zhou, C., Kennedy, B. K. (2018 Mar 8). The yeast replicative aging model. Biochim Biophys Acta. (Epub ahead of print)
- Ruan, L.*, Zhou, C.*, et al. (2017). Cytosolic proteostasis via importing of misfolded proteins into mitochondria. Nature, 543(7645), 443–446. (*Equal contribution)
- Zhou, C., et al. (2014). Organelle-based aggregation and retention of damaged proteins in asymmetrically dividing cells. Cell, 159, 530–542. PMID: 25417105.
- Zhou, C., et al. (2014). Life history: Mother-specific proteins that promote aging. Curr Biol, 24, 24, R1162-4.
- Zhou, C., et al. (2011). Motility and segregation of hsp104-associated protein aggregates in budding yeast. Cell, 147, 1186–1196.