Nat.Immu：免疫耐受和免疫排斥的新机制被发现

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作者简介：

Mark L. Kahn
Assistant Professor, Dept of Medicine, Division of Cardiology

Cell Biology and Physiology Program

Research Interests

• Signaling pathways in angiogenesis and hemostasis.

Key words: Platelet, signaling, angiogenesis, vascular development, integrin, Syk, SLP-76.

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Description of Research

My laboratory investigates signaling pathways in cardiovascular development and function. We have two general areas of interest: angiogenesis and platelet signaling. In some cases, e.g. the role of Syk and SLP-76 signaling downstream of platelet collagen receptors and during lymphatic vasculard development, these areas intersect but in others we pursue independent questions. Major projects in the lab include the following:

1. Regulation of lymphatic vascular development by Syk and SLP-76 signaling. Mice lacking Syk or SLP-76 exhibit lethal vascular phenotypes that we have recently found to be due to a failure to separate emerging lymphatic vessels from pre-existing blood vessels. Genetic studies using conditional alleles, embryo chimeras and transgenic rescue indicate that the pathway regulates hematopoietic endothelial precursor cells that contribute to lymphatic development. The long term goals of this project are to understand the contribution of the hematopoietic system to vascular development and to branch out to investigate other signaling pathways required specifically for lymphatic vascular development.
2. Integrin and immunoreceptor signaling in platelet collagen responses. Activation of platelets at sites of arterial injury is the first step in a chain of molecular and cellular events that culminate in heart attack and stroke. A primary activating ligand in this setting is collagen, a matrix protein exposed by vessel injury. Collagen activation of platelets is initiated by the glycoprotein VI receptor, a homologue of immune receptors expressed exclusively on platelets and coupled to Syk and SLP-76 through an ITAM. A second receptor for collagen on platelets is the integrin a2b1 which is also thought to activate Syk and SLP-76 signals. We are presently using mouse genetic models and engineered hematopoietic cell lines developed in our laboratory to determine how these two structurally distinct receptors coupled to a common intracellular signaling pathway in response to collagen. Recent studies using gene targeting of the beta 1 integrin chain have also revealed novel developmental roles for integrin signaling that are being studied.
3. Genetic transduction of fluid flow forces by Klf2 in endothelial cells in vivo. Fluid hemodynamic forces regulate vascular responses in adult animals and are believed to also contribute to vessel formation and growth during development. Klf2 is a transcription factor expressed in endothelial cells in response to fluid shear forces. Using conditional Klf2 mice developed in the lab we are investigating the pathways by which hemodynamic forces regulate vascular development and function.

Recent Publications

Abtahian F, Guerriero A, Sebzda E, Lu M, Mocsai A, Myers E, Huang B, Jackson D, Ferrari A, Tybulewicz V, Lowell A, Lepore J, Koretzky G, Kahn ML. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 2003 299(10): 247-251.

Chen,H and Kahn, M.L. Reciprocal signaling by integrin and non-integrin receptors during collagen activation of platelets. Molecular and Cellular Biology, 2003 23 (14) 4767-4777.

Xu, B., deWaal, R., Mor-Viknin, N., Hibbard, C., Markovitz, D.M., Kahn, M.L. The endothelial-specific antibody PAL-E identifies a secreted form of vimentin in the blood vasculature. Molecular and Cellular Biology, 2004 Oct;24(20):9198-9206.

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