Our laboratory focuses on the understanding of two fundamental biological processes that affect virtually every aspect of cellular physiology: calcium signalling and protein folding. Our research has implications for a number of human diseases including vascular disease such as heart attack, neurodegenerative diseases such as Alzheimer’s, and systemic diseases such as cancer.
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. The multifunctional nature of the ER has enabled us to help identify the contribution of several ER associated proteins to the maintenance of ER homeostasis in health and disease. 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.
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.