Our lab studies the structure and function of endoplasmic reticulum (ER) membranes and the role of this membrane system in the control of intracellular signalling, communication with other intracellular organelles, regulation of protein synthesis and folding, modulation of gene expression and calcium homeostasis. The ER plays a vital role in many cellular processes, including calcium signaling lipid biosynthesis; and protein synthesis, folding, and post-translational modification. Most importantly, the ER can detect and integrate incoming signals, generate output signals in response to environmental changes, and can even modulate its own luminal dynamics. How the ER affects the balance between anti- versus pro-apoptotic signals, and therefore between adaptive and maladaptive cellular responses, remains a crucial question in pathophysiology and in cell biology. ER stress is associated with many severe human pathologies including heart disease, metabolic disorders, cancer and neuropathies. We discovered that ER resident chaperones play critical roles in cardiac development and pathophysiology of the mature heart. The proteins are also key in specific neuropathies. Currently, the focus of our lab is on the role of ER associated molecular chaperones (calreticulin, calnexin and others) and ER stress in cardiac and nervous system physiology and pathophysiology. Our long-term goal is to understand ER stress and ER signaling events responsible for the activation and maintenance of intracellular pathways affecting cardiac or neuronal physiology and pathology, and to use this information to devise pharmacological and genetic therapies for the treatment of human disease.
To learn more about our research, read this interview/article in International Innovation here.
Here are a few examples of research projects currently being pursued in our lab:
Modulators of ER Stress
Using small interfering RNA (siRNA) library screens, we have identified several cellular proteins that regulate ER stress responses and the unfolded protein response (UPR), including ER luminal resident chaperones and folding enzymes. We are pursuing a variety of strategies to use this information to manipulate ER stress pathways and to uncover additional regulators of ER stress.
Calreticulin, ER Resident Proteins and Cardiac Physiology
We apply gene knockout and transgenic techniques to understand the role of ER proteins and the ER luminal environment in embryogenesis and congenital pathologies. We discovered that calreticulin is critical for cardiac development. Modulation of calreticulin expression in the heart results in development of severe cardiomyopathies and complete heart block. We are investigating the contribution of calreticulin and other ER resident proteins to cardiac pathology including cardiac hypertrophy and heart failure.
ER Calcium Homeostasis
Calcium is released from the ER into the cytoplasm and the loss of ER calcium stores necessitates refilling via a process known as store-operated calcium entry (SOCE). Stromal interaction molecule 1 (STIM1) is an ER membrane calcium sensor responsible for activation of store-operated calcium influx. We discovered that STIM1 oligomerization and SOCE are modulated by the ER resident oxidoreductase PDIA3. We also discovered that ER calcium status is important determinant of the basal sensitivity of the sterol sensing mechanism inherent to the SREBP processing pathway. We are interested in understanding the role of ER luminal environment in calcium signaling and in the regulation cholesterol metabolism.
Deciphering a Role of ER Chaperones in Neuropathies
We discovered that calnexin-deficient mice develop a specific neuropathy, dysmyelination and impaired motor function. We identify calnexin in brain endothelial cells as a novel target for developing strategies aimed at managing or preventing the pathogenic cascade that drives neuroinflammation and destruction of the myelin sheath in multiple sclerosis. We are interested in understanding the role of calnexin and ER stress in the pathology of the nervous system with a special emphasis on human neuropathies and myelin diseases.