Grant: Discovery Grants Program - Individual

The long-term goal of my research program is to better understand the roles played by a particular family of proteins (called TAAR) in maintaining normal cell function in the body. This family of proteins detects a series of chemicals (called trace amines) that can be produced by the body, released from microorganisms normally found in the body, or ingested as part of commonly consumed foods. Following detection of these chemicals, TAAR then alter the activity of cells. Much of the existing research has focussed on how brain function is affected, with very little known about how cells outside of the brain respond to the detection of trace amines by TAAR. Advancing this understanding is the focus of the current proposal. Our previous work has shown that the location of TAAR in cells of the immune system is variable. Why this occurs, and what controls this variability is unknown. In the first part of this proposal we will use cutting-edge gene editing techniques to create TAAR proteins that are easy to track as they move around cells, and use these to identify the location of TAAR in real time in immune cells receiving different physiological signals (eg. pro-inflammatory and anti-inflammatory). This will allow us to then identify what the molecular partners are that cause TAAR to be in different places in different situations. To better understand what the physiological consequences are of TAAR in immune cells, we will expand on our previous work that identified a novel interaction between TAAR activation and naturally occurring pro-inflammatory signals. While this work suggests that TAAR can dampen these pro-inflammatory signals, the precise mechanism is not known. In the second part of this proposal we will identify the molecular basis by which TAAR interacts with, and modifies, pro-inflammatory signals. Finally, the variable localization of TAAR includes various places inside cells. This requires that there are processes to allow trace amines to enter cells in order to activate TAAR. Our previous work has made considerable progress in determining these processes, but the identity of some of the proteins that transport trace amines in to cells has remained elusive. In the final aim of this proposal we will identify these transporter proteins. By filling these knowledge gaps the understanding of how trace amines and TAAR affect cell responses outside of the brain will be advanced. This will not only increase understanding of the normal mechanisms by which cell activity is maintained within physiological limits, but also identify new processes through which microorganisms and nutrients can affect human physiology, in particular with respect to the immune system. This will improve our understanding of host-nutrient-microbe interactions, a critical first step to allow future translational research related to environmental hypersensitivity disorders such as inflammatory bowel disease, that is beyond the scope of the current proposal.