Signaling pathways in angiogenesis and hemostasis.
Angiogenesis, vascular development, platelet, signaling.
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 these areas intersect, e.g. the role of Syk and SLP-76 signaling downstream of platelet receptors that regulate lymphatic vascular development. 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. We have recently identified platelet interaction with lymphatic endothelial cells as the basis for this mechanism of vascular regulation. The long term goals of this project are to understand how platelets control endothelial function and lymphatic vascular development. Platelet immunoreceptor signaling. There are two platelet-specific immune-type receptors, GPVI and CLEC2, that activate Syk and SLP-76 signals. GPVI is a collagen receptor that functions in hemostasis and thrombosis. CLEC2 is a receptor for the lymphatic endothelial protein PDPN and regulates blood-lymphatic vascular interactions. We are presently using mouse genetic models to understand how these two receptors signal and to define their biological roles in vivo. Role of cerebral cavernous malformation (CCM) signaling pathway in vascular development and disease. CCMs are a common human vascular disease caused by loss of function mutations in 3 CCM proteins. We have recently shown that the Heart of Glass (HEG) receptor and CCM proteins are required in mouse and fish cardiovascular development. We are actively investigating how this recently identified pathway regulates endothelial function in development and causes CCMs.
1. Regulation of lymphatic vascular development by platelet signaling. 2. HEG-CCM signaling in fish and mouse models. 3. Novel receptor signaling pathways in mammalian cardiovascular development. 4. Development and application of lymphatic endothelial-specific gene knockouts.
Xiangjain Zheng, PhD-postdoctoral fellow; Zhiyng Zou, PhD-postdoctoral fellow; Cara Bertozzi, PhD student; Chiu-Yu Chen, MD-PhD student; Alec Schmaier, PhD student; Chong Xu, PhD-postdoctoral fellow; Jiping Xiao, PhD-postdoctoral fellow; Patricia Mericko, Lab Manager; Mei Chen Research, Specialist.
Bui Hung M, Enis David, Robciuc Marius R, Nurmi Harri J, Cohen Jennifer, Chen Mei, Yang Yiqing, Dhillon Veerpal, Johnson Kathy, Zhang Hong, Kirkpatrick Robert, Traxler Elizabeth, Anisimov Andrey, Alitalo Kari, Kahn Mark L: Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD. The Journal of clinical investigation May 2016.
Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, Arthur JS, Whitehead KJ, Awad IA, Li DY, Zheng X, Kahn ML: Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signaling. Nature 532(7597): 122-6, April 2016.
Maltzman Jonathan S, Reed Hasina Outtz, Kahn Mark L: HA-ving lymphatics improves lung transplantation. The Journal of clinical investigation 125(11): 3999-4001, Nov 2015.
Sweet DT, Jiménez JM, Chang J, Hess PR, Mericko-Ishizuka P, Fu J, Xia L, Davies PF, Kahn ML: Lymph flow regulates collecting lymphatic vessel maturation in vivo. Journal of Clinical Investigation 125(8): 2995-3007, Aug 2015.
Kahn Mark L: Vascular development for climate control. Developmental cell 33(3): 241-2, May 2015.
Yang Yiqing, Enis David, Zheng Hui, Chia Stephanie, Yang Jisheng, Chen Mei, Dhillon Veerpal, Papayannapoulou Thalia, Kahn Mark L: Cell adhesion mediated by VCAM-ITGa9 interactions enables lymphatic development. Arteriosclerosis, Thrombosis, and Vascular Biology 35(5): 1175-89, Mar 2015.
Kahn Mark L: A critical role of platelet glycoprotein ibα in arterial remodeling. Arteriosclerosis, Thrombosis, and Vascular Biology 35(3): 498-9, Mar 2015.
Zhou Zinan, Rawnsley David R, Goddard Lauren M, Pan Wei, Cao Xing-Jun, Jakus Zoltan, Zheng Hui, Yang Jisheng, Arthur J Simon C, Whitehead Kevin J, Li Dean, Zhou Bin, Garcia Benjamin A, Zheng Xiangjian, Kahn Mark L: The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression. Developmental Cell 32(2): 168-80, Jan 2015.
Jakus Zoltán, Gleghorn Jason P, Enis David R, Sen Aslihan, Chia Stephanie, Liu Xi, Rawnsley David R, Yang Yiqing, Hess Paul R, Zou Zhiying, Yang Jisheng, Guttentag Susan H, Nelson Celeste M, Kahn Mark L: Lymphatic function is required prenatally for lung inflation at birth. The Journal of Experimental Medicine 211(5): 815-26, May 2014.
Zheng Xiangjian, Riant Florence, Bergametti Françoise, Myers Cynthia D, Tang Alan T, Kleaveland Benjamin, Pan Wei, Yang Jisheng, Tournier-Lasserve Elisabeth, Kahn Mark L: Cerebral cavernous malformations arise independent of the heart of glass receptor. Stroke: A Journal of Cerebral Circulation 45(5): 1505-9, May 2014.
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Last updated: 10/17/2016
The Trustees of the University of Pennsylvania