Contact information
Email:听sal.carbonetto [at] mcgill.ca
Academic affiliations
Professor Emeritus听|听Neurology & Neurosurgery, Medicine (听&听Faculty)
No longer accepting new lab members.
听
Research
Dystrophin Associated Proteins in Synapse Formation and Muscular Dystrophy
Dystrophin is a cytoskeletal protein that is linked to dystroglycan in the plasma membrane to form the functional core of a larger, supramolecular complex that is expressed in muscle, brain and other tissues. Mutations in dystrophin and dystroglycan result in muscular dystrophies as well as in defects in neuromuscular synapses. Duchenne Muscular Dystrophy, which results from mutations in the dystrophin gene, often is accompanied by some mental retardation. Work from the Carbonetto lab is aimed at understanding the role of dystroglycan, dystrophin and associated proteins in muscle function/dysfunction, and in synaptic transmission. These studies require a range of techniques from protein biochemistry, to immunohistochemistry, recombinant DNA approaches and targeted mutations in mice. Research on muscle function focus on how dystroglycan maintains muscle integrity. Mutational analysis of the dystroglycan gene in a transgenic mouse model will identify regions of the protein which are implicated in muscular dystrophy. Other work is aimed at the pathways of cell death regulated by dystroglycan in muscle cells in culture. Studies on synapses utilize the neuromuscular junction as a model to explore how dystroglycan stabilizes acetylcholine receptors and acetylcholinesterase in the postsynaptic membrane. In addition dystroglycan levels regulate nerve terminal size. Thus changes in this complex may well be important in changes responsible for synaptic plasticity. Finally, we have identified a novel complex of dystrophin associated proteins in the brain which functions synaptically in vesicle recycling and may be relevant to the mental retardation associated with some muscular dystrophies.
听
Contact information
Email:听sam.david [at] mcgill.ca
Academic affiliations
Professor |听Neurology & Neurosurgery, Medicine (听&听Faculty)
Researcher |听
Associate Member |听Dept. of Anatomy and Cell Biology
No longer accepting new lab members.
Research
Sam David鈥檚 laboratory is engaged in research in 3 areas:
(1) CNS and Peripheral Nerve Injury. This work is focused on understanding the cellular changes and molecular mechanisms that trigger, as well as, switch off inflammation after CNS (spinal cord) and peripheral nerve injuries. We have identified several molecules that mediate inflammation after spinal cord injury and contribute to secondary tissue damage (neuronal loss and myelin damage). These include proteases, lipases, kinases, adhesion molecules and chemokines/cytokines. We also test small molecule compounds to target these inflammatory mediators to promote functional recovery after spinal cord injury. We also study the molecular mechanisms underlying the switching off of the inflammatory response after peripheral nerve injury and assess how these mechanisms operate in the CNS.
(2) Multiple Sclerosis. Our work on MS deals with the role of the phospholipase A2 (PLA2) family in the onset and progression of CNS autoimmune disease in mice called experimental allergic encephalomyelitis (EAE). This work has led to the discovery of excellent therapeutic targets for the treatment of the relapsing-remitting form of MS. Our current work is directed at testing new generation PLA2 inhibitors in vivo; the role of suppressors of cytokine signalling (SOCS) in chronic forms of EAE; and the role of molecules involved in iron homeostasis in the pathogenesis of EAE.
(3) Neurodegenerative Disease. This work focuses on the role of the ferroxidases in preventing iron accumulation and iron-mediated free radical injury in the CNS. Lack of these enzymes results in iron deposition and neurodegeneration in the CNS. We have identified and cloned a GPI-anchored form of a ferroxidase (ceruloplasmin), which is expressed by astrocytes in the CNS, and have generated a ceruloplasmin gene knockout mouse. We are currently characterizing other ferroxidases in the CNS; and the role of the iron efflux transporter, ferroportin, in the CNS. We are also studying the involvement of these iron homeostasis proteins in spinal cord injury and in mouse models of ALS and MS.