Mitoflash frequency as a unifying lifespan predictor. This work supports a coupling between the mitochondrial function and the process of aging, and lend credence to aging theories that place mitochondria at a nodal point of lifespan regulation.
This work suggests that CAMKII (UNC-43) and Calcineurin (TAX-6•CNB-1), by phosphorylating or de-phosphorylating serine 286 of C. elegans FoxO, DAF-16, extend or shorten the lifespan of C. elegans.
This work has developed pLink, software for data analysis of cross-linked proteins coupled with mass-spectrometry analysis
Basic Mechanisms of Aging
On the biology side, our lab is interested in understanding the regulatory mechanisms of aging using C. elegans as a model. We quantify mRNA and protein abundance changes during the aging process of wild type and long-lived C. elegans mutants, and ask how they differ. We also analyze what happens to sub-cellular organelles such as mitochondria during aging. By cataloging such changes, we hope to describe the aging process in more detail, and lay the foundation for further investigations about the regulation of aging. At the center stage of our aging research is the Insulin/IGF-1 Signaling (IIS) pathway. Although it has been shown that components of the IIS pathway, from the insulin receptors to the FoxO transcription factors, all have important functions in lifespan regulation, the exact target genes downstream of FoxO that are responsible for the longevity of IIS mutants remain unclear. We are particularly interested in finding out those targets and then discerning the connections amongst them so that one can begin to understand the extraordinary effect of IIS on lifespan. We are also actively studying post-translational modifications (PTM) of DAF-16, which is the C. elegans FoxO. This key transcription factor is intricately regulated by a battery of kinases and a couple of phosphatases, including calcineurin, a calcium-and-calmodulin-dependent Ser/Thr phosphastase. The questions we are trying to address include how different environmental and internal cues (e.g. developmental stages) affect PTMs of DAF-16, and how the "modification code" of DAF-16 alters its transcriptional activity.
Mass Spectrometry Based Proteomic Techniques
On the mass spectrometry (MS) front, our goal is to use and develop MS-based proteomic techniques to help answer biological questions. Besides protein identification, we routinely carry out quantitative proteomics analysis and PTM analysis of samples as complex as cell lysates. In collaboration with other researchers including the pFind group at the Institute of Computing Technology, we are currently developing methods to sequence peptides de novo (i.e. without searching a protein sequence database), to improve peptide identification from ETD spectra, and to probe protein-protein interactions by crosslinking followed by MS identification. The lab is equipped with four mass spectrometers, a Q Exactive, an LTQ-orbitrap with ETD, an ion trap instrument HCTultraPTM, and a triple-quadruple instrument TSQ Discovery.