Trimble Lab
The Trimble lab is located within the SickKids Research Institute Cell Biology Program on the 19th floor of the state-of-the-art PCGRL (Peter Gilgan Centre for Research and Learning) building, in the heart of downtown Toronto.
Septins
Only recently have the filamentous septin family of GTPases been recognized to be the fourth component of the cytoskeleton, and their interactions with other cytoskeletal proteins, as well as a host of other molecules, allow them to function as signaling platforms for many critical cellular processes. Alterations in septin experssion patterns have been linked to cancer and mutations in septins have been associated with human diseases such as male infertility and hereditary neuralgic amyotrophy. Ongoing projects in the laboratory are aimed at understanding the mechanisms controlling septin filament assembly, their contributions to signal transduction, and their specific roles in cytokinesis and cell migration.
Primary cilia
The primary cilium is a central signaling structure, likened to the cellular “antenna”, found on most cells of the body. Defects in cilia formation lead to a range of diseases and ongoing studies are aimed at investigating how cilia are formed, what controls their length, and how this is associated with their signal transduction activities. For these studies we are using cell culture and animal models including mice and zebrafish.
Lipid transport via scavenger receptors
The SCARB family of scavenger receptors (CD36, SR-B1 and LIMP II) are broadly expressed proteins that serve as receptors for a number of ligands including the lipoproteins HDL and LDL. These lipoproteins control the homeostatic balance of cholesterol levels in the body and their proper function is important for protection against atherosclerosis. By determining the crystal structure of the SCARB receptors we and our collaborators showed that they contain a hydrophobic tunnel through which cholesterol can directly transit from the lipoprotein to the plasma membrane. Future studies will involve further characterization of this novel mode of lipid transport, and determination of the relative contributions of endocytosis and direct transport in cholesterol homeostasis. Image: Space-filling model of SR-B1 with cholesterol molecules (orange) traversing the hydrophobic tunnel (yellow) directly into the plasma membrane (white). Courtesy of Christopher Collins.
SNARE-mediated membrane fusion
We have a longstanding interest in understanding the mechanisms controlling membrane fusion by the SNARE proteins and their regulation. In particular, recent work has focused on the AAA ATPase NSF which functions as a helicase to unwind the SNARE complex. Future directions will involve characterizing the role of APT hydrolysis in NSF helicase activity and the development of novel methods to monitor protein conformational changes.