Grant: Discovery Grants Program - Individual

The goal of my research is to understand the human aging process. Body tissues are made up of cells that contain different types of proteins that can get damaged and misfolded over time via a process called `degenerative protein modification' (DPM). When proteins get damaged by DPMs they often stop working properly, but in some cases they can also take on harmful new functions. In our research, we study the different types of DPMs that can take place in the human body as we get older, then test how these structural changes influence normal cell activities. It has been known for a long time that DPMs play important roles in human aging, but we do not yet understand how these changes can eventually stop body tissues from working normally. This is mainly due to the challenges of studying DPMs in human biosamples, which are complex mixtures that need to be handled very carefully to avoid causing further protein damage outside the body. In addition, the current technical and scientific methods are not sensitive enough to study or understand the function of DPMs in the aging process. For these reasons, analysing DPMs in human samples is extremely complicated, and figuring out how individual damaged proteins can modify tissue function is not straightforward. My research team has therefore developed new methods of measuring protein levels and DPM profiles in human cells and tissues, as well as testing their functions in cells so that we can better understand the aging process. Using these approaches, we recently made a striking discovery that important human proteins change over time to produce abnormal structures called isoAsp-Gly-Arg (isoDGR) motifs which cause harmful effects by inducing chronic low-grade inflammation known to drive human aging. Since protein damage typically impairs the protein's normal activity, this surprising new `gain-of-function' change represents a completely novel understanding of the aging process. We think that further research in this ground-breaking field will discover more DPM-induced harmful effects inside the body that causes human aging. Therefore, in this proposal we are focusing on three specific types of DPMs (i.e., deamidation, carbamylation, and thiol trioxidation) that we think can introduce harmful new protein functions as body tissues age. Our major aim is to develop new research tools that allow us to accurately study these challenging DPM types in human samples so that we can better understand human aging. Moreover, this proposal will train students with advanced technical skillsets and provide them with research experience and leadership opportunities to the benefit of Canadian research and industry.