Pièce : Rm. 1452, RGN
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Senior Scientist, Neuroscience, Ottawa Hospital Research Institute
Associate Professor, Department of Medicine, University of Ottawa
Associate Professor (adj.), Department of Cellular and Molecular Medicine
Associate Professor (adj.), Graduate Program of Pathology and Experimental Medicine
Core member, Centre for Stroke Recovery
The brain controls how much we eat, when we feel fed, and how our body uses the calories consumed. Modern fat-rich diet undermines this brain function and contributes to over-eating and obesity. More than one third of Canadians are obese. Obesity causes diabetes, elevating the risk of stroke and Alzheimer's disease. Anxiety affects 12% of Canadian population and anxiety disorders are prevalent in people with obesity-associated diabetes. My laboratory is working to identify the common molecular links between metabolic disorders, stroke, Alzheimer's disease and anxiety in order to develop common therapies to restore healthy brain function.
A central theme of my laboratory is to understand how transcription and signaling molecules regulate synaptic plasticity to control learning, memory and metabolic homeostasis. One of the long-term objectives of the current research program is to identify and characterize how the function of hypothalamic neurons and microglia and their interaction are regulated by energy status and early life experience to influence metabolic homeostasis. The experimental tools used include transgenic mouse models, behavior studies, cell culture, molecular biology, biochemical studies and electrophysiological recording in acute brain slices. In the past 7 years, with the support of the CFI, CIHR, HSFC, and CDA, my laboratory has generated several transgenic mouse models and identified LMO4 as a novel transcription and signaling molecule that regulates synaptic plasticity and participates in (hypothalamic) neural control of metabolism. Recently, we further identified IRF2BP2 (Interferon regulatory factor-2 binding protein 2) as a key modulator of the innate immune response and participating in synaptic pruning. Two lines of research focus on how LMO4 and IRF2BP2 are involved in these processes using several lines of transgenic mice that we generated.
Project 1. Neural control of metabolism.
Metabolic homeostasis is orchestrated by the hypothalamus through the neuroendocrine and the autonomic nervous systems. Leptin, a hormone produced from fat cells, acts on a specific area of the brain to reduce feeding, increase fat metabolism, and improve insulin sensitivity. Although most obese people have higher levels of leptin in their blood, its effects are reduced, a condition called central leptin resistance. Our recent article reports that LIM domain only 4, LMO4, is a novel gene participating in central leptin signaling (Fig. 1). We are currently working to determine how LMO4 regulates leptin-dependent control of peripheral insulin sensitivity. We have generated transgenic mice that specifically delete LMO4 in glutamatergic neurons, in GABAergic neurons, in neurons of the paraventricular nucleus and in the ventromedial hypothalamic nucleus. Each mouse line has a unique metabolic phenotype. Using patch-clamp electrophysiological recording and an optogenetic system, we are mapping neural circuits that control feeding behavior and metabolic homeostasis. This research could help find a way to restore leptin sensitivity which is a key challenge in treating obesity and type 2 diabetes. We are also using these mouse models to screen for drugs that restore leptin signaling.
Project 2. Molecular mechanisms controlling synaptic plasticity and anxiety disorders.
Our published work (Figs. 2, 3) indicates that loss of LMO4 impairs the function of the intracellular calcium channel ryanodine receptor (RyR) resulting in impaired learning and memory and may contribute to the early progression of Alzheimer's disease. In addition, our data indicates that LMO4 plays a critical role in anxiety and fear memory extinction, a form of learning to dissociate anxiety from a previous traumatic fear memory. Using electrophysiological, behavioral and pharmacological approaches with transgenic mouse models, we are identifying novel signaling pathways and drugable targets to treat anxiety disorders.
Project 3. Modulation of innate immunity to improve recovery from stroke.
Stroke results in an abrupt deprivation of oxygen and nutrients, causes neuronal cell death and triggers a cascade of inflammatory signals that contribute to secondary brain damage. The interaction between neurons and microglia, the resident macrophages of the brain, plays a critical role in the response to ischemic brain injury and the outcome of recovery. In addition to their well-characterized involvement in the innate immune response to infection and inflammation in response to brain injury, microglia are emerging as key modulators of neuronal function by participating in synaptic pruning. Synaptic pruning is a process that eliminates unused synapses in the brain to optimize its function. The pruning process occurs on a large scale in the developing brain but continues to take place in the adult brain, and is important for learning and memory during the healthy state as well as for recovery from stroke injury. Depending on local cues and cytokines, microglia become polarized to a pro-inflammatory M1 or an anti-inflammatory reparative M2 phenotype, through processes that are incompletely understood. Little is known about how M1 or M2 microglia differentially regulate synaptic pruning and remodeling.
We identified a novel innate immune response regulator IRF2BP2 (interferon regulatory factor 2 binding protein 2) that is induced by hypoxia in neurons and microglia. Our data suggests that IRF2BP2 promotes M2 microglia/macrophage polarization either indirectly via its neuronal influence or directly via its function in these innate immune cells. IRF2BP2 is a co-repressor of IRF2 and NFAT1 (nuclear factor of activated T cells), key transcription factors regulating inflammation and the innate immune response. We have established neuron-specific knockout mice and microglia/macrophage-specific knockout mice. These two novel mouse models provide us a unique opportunity to elucidate signaling pathways controlling microglia polarization and to identify therapeutic targets to facilitate neural network rewiring and functional recovery from stroke injury.
synaptic plasticity, hypothalamus, diabetes, stroke, innate immunity, metabolism, atherosclerosis