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Mark
L. Kahn
Assistant Professor, Dept of Medicine, Division of Cardiology
Cell
Biology and Physiology Program
Address
952 BRB II/III
421
Curie Blvd, Room 952
Philadelphia, PA 19104
Office tel.: 215 898-9007
Lab tel.: 215 573-7142
Fax: 215 573-2095, 2094
E-mail: markkahn@mail.med.upenn.edu
Link(s)
Dr.
Kahn's lab webpage
Education
Brown University: BA (Biology), 1984.
Brown University : MD (Medicine), 1987.
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Research
Interests
- Signaling pathways in angiogenesis and hemostasis.
Key words: Platelet, signaling, angiogenesis,
vascular development, integrin, Syk, SLP-76.
Search PubMed for articles
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:
- 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.
- 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.
- 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.
Chen H, Zou Z, Sarratt KL, Zhou D, Zhang M,
Sebzda E, Hammer DA, Kahn ML. In vivo beta1 integrin function
requires phosphorylation-independent regulation by cytoplasmic
tyrosines. Genes and Development. 2006 Apr 15;20(8):927-32.
Sebzda E, Hibbard C, Sweeney S, Abtahian F,
Bezman N, Clemens G, Maltzman J, Cheng L, Zhou D, Turner M,
Tybulewicz V, Koretzky GA, Kahn ML. Syk and Slp-76 mutant
mice reveal a cell autonomous hematopoietic cell contribution
to vascular development. Developmental Cell, 2006
in press.
Lab
Rotation
Projects for 2006-2007
- Role of Syk and SLP-76 signaling in bone
marrow derived endothelial cells.
- Integrin outside-in signaling in platelets
and hematopoietic cells.
- Collagen receptor function in platelets.
- Activation of Klf2 by hemodynamic shear
and its role in vascular development and atherosclerosis.
- Novel receptor signaling pathways in mammalian
cardiovascular development.
- Development and application of lymphatic
endothelial-specific gene knockouts.
- Lab personnel:
- John Lee, MD, PhD postdoctoral fellow
Eric Sebzda, PhD postdoctoral fellow
Shawn Sweeney, PhD postdoctoral fellow
Bin Xu, PhD postdoctoral fellow
Xiangjain Zheng, PhD postdoctoral fellow
Zhiyng Zou, PhD postdoctoral fellow
Cara Bertozzi PhD student
Chiu-Yu Chen MD-PhD student
Ben Kleaveland MD-PhD student
Chris Hibbard premed student
Patricia Mericko Lab Manager
Mei Chen Research Specialist
last updated 7/2006
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