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Christian Waeber, Ph.D.
Neuroscience Center at Massachusetts General Hospital

Massachusetts General Hospital – East
Building 149
13th Street
Charlestown, MA 02129

Telephone: 617-726-0768
Email: waeber@helix.mgh.harvard.edu


Biography
Dr. Waeber received his Ph.D. from the University of Fribourg in Switzerland and postdoctoral training in neuroscience from the University of Montpellier, France before joining the Massachusetts General Hospital.

Research Program
Research Description: Our laboratory is interested in characterizing membrane receptors and signal transduction pathways controlling blood vessel tone in the brain. Modulators released by neurons or glial cells, either during normal brain activation or under pathologic conditions such as stroke, seizure or possibly migraine, are known to act on vascular cells, leading to vasoconstriction or vasodilation. Our research in the last few years has focused on one of these modulators, the lipid sphingosine-1-phosphate (S1P; Figure 1), which acts on several subtypes of G protein-coupled receptors termed S1P1, S1P2, S1P3, S1P4 and S1P5 (formerly Edg-1, -5, -3, -6 and -8) and activated a complex signaling system in vascular endothelial cells (see Figure 2).

We have shown that S1P selectively constricts cerebral, but not peripheral arteries via S1P3 receptors (Salomone et al, 2003). The brain is one of the organs containing the highest concentration of S1P, and we have shown that one of the S1P-synthesizing enzymes, sphingosine kinase 2, is the predominant isoform in neurons. In addition to constricting brain blood vessels, S1P also stimulates proliferation of vascular cells (endothelial cells and smooth muscle cells, and protects them from ischemia induced cells death. We hypothesize that in the normal brain or under pathological conditions such as ischemia, brain cells release significant amounts of S1P that controls vascular tone, protects from ischemia-induced cell death, and induces repair mechanisms. All three actions are particularly important in the context of cerebral ischemia (stroke).
We have shown that activating brain S1P receptors, either using pharmacological treatment with fingolimod, or by activating endogenous S1P synthesis (preconditioning) protects the brain from the consequences of brain ischemia.

We are currently investigating the role of the immune response in the beneficial effects of fingolimod in rodent models of stroke.

 

Relevant publications:

• Yung LM, Wei Y, Qin T, Wang Y, Smith CD, Waeber C. (2012) Sphingosine Kinase 2 Mediates Cerebral Preconditioning and Protects the Mouse Brain Against Ischemic Injury. Stroke 43:199-204.

• Wei Y, Yemisci M, Kim HH, Yung LM, Shin, HK, Hwang SK, Guo S, Qin T, Alsharif N, Brinkmann V, Liao JK, Lo EH, Waeber C (2011) Fingolimod provides long-term protection in rodent models of cerebral ischemia, Annals Neurol. 69:119-29.

• Hopson KP, Truelove J, Chun J, Wang Y, Waeber C. (2011) S1P activates store-operated calcium entry via receptor- and non-receptor-mediated pathways in vascular smooth muscle cells, Am J Physiol Cell Physiol. 300:C919-26.

Salomone S, Potts EM, Tyndall S, Ip PC, Chun J, Brinkmann V, Waeber C. (2008) Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools. Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Br J Pharmacol. 153:140-7.

Waeber, C, Blondeau, N, Salomone S (2004) Vascular sphingosine-1-phosphate S1P1 and S1P3 receptors. Drug News and Perspective, 17:365-382.

Harada J, Foley M, Moskowitz MA, Waeber C. (2004) Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells. J Neurochem. 88:1026-39.

Waeber C, Moskowitz MA. (2003) Therapeutic implications of central and peripheral neurologic mechanisms in migraine. Neurology. 61:S9-20.

Salomone S, Yoshimura S, Reuter U, Foley M, Thomas SS, Moskowitz MA, Waeber C. (2003) S1P3 receptors mediate the potent constriction of cerebral arteries by sphingosine-1-phosphate. Eur J Pharmacol. 469:125-34.

Waeber C, Chiu ML. (1999) In vitro autoradiographic visualization of guanosine-5'-O-(3-[35S]thio)triphosphate binding stimulated by sphingosine-1-phosphate and lysophosphatidic acid. J Neurochem. 73:1212-21.

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