Description of Research Expertise

Research Interests
Signaling pathways in angiogenesis and hemostasis.

Key words: 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.

Rotation Projects
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.

Lab personnel:
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.

Selected Publications

Jabarkheel R, Li L, Frankfurter M, Zhang DY, Gajjar A, Muhammad N, Srinivasan VM, Burkhardt JK, Kahn M: Untangling sporadic brain arteriovenous malformations: towards targeting the KRAS/MAPK pathway Front Surg. : 2024.

Ren J, Cui Z, Jiang C, Wang L, Guan Y, Ren Y, Zhang S, Tu T, Yu J, Li Y, Duan W, Guan J, Wang K, Zhang H, Xing D, Kahn ML, Zhang H, Hong T: GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas Am J Hum Genet : 2024.

Yuki K, Vallon M, Ding J, Rada CC, Tang AT, Vilches-Moure JG, McCormick AK, Henao Echeverri MF, Alwahabi S, Braunger BM, Ergün S, Kahn ML, Kuo CJ: GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism Development : 2024.

Kahn ML: CCM Function in the Heart: Working From Outside-In Rather Than Inside-Out JACC Basic Transl Sci : 2024.

Li Y, Girard R, Srinath A, Cruz DV, Ciszewski C, Chen C, Lightle R, Romanos S, Sone JY, Moore T, DeBiasse D, Stadnik A, Lee JJ, Shenkar R, Koskimäki J, Lopez-Ramirez MA, Marchuk DA, Ginsberg MH, Kahn ML, Shi C, Awad IA: Transcriptomic signatures of individual cell types in cerebral cavernous malformation Cell Commun Signal : 2024.

Ocskay Z, Bálint L, Christ C, Kahn ML, Jakus Z: CCBE1 regulates the development and prevents the age-dependent regression of meningeal lymphatics Biomed Pharmacother : 2024.

Gao S, Thillaikumaran T, Dominguez MH, Giang W, Hayes K, Chen X, Pace J, Bockman J, Jathan D, Sung D, Narayan S, Frankfurter M, Mericko-Ishizuka P, Yang J, Castro M, Potente M, Kahn ML: YAP/TAZ signaling in allantois-derived cells is required for placental vascularization bioRxiv : 2024.

Li L, Ren AA, Gao S, Su YS, Yang J, Bockman J, Mericko-Ishizuka P, Griffin J, Shenkar R, Alcazar R, Moore T, Lightle R, DeBiasse D, Awad IA, Marchuk DA, Kahn ML, Burkhardt JK: mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice Stroke : 2023.

Gao S, Tang AT, Wang M, Buchholz DW, Imbiakha B, Yang J, Chen X, Hewins P, Mericko-Ishizuka P, Leu NA, Sterling S, August A, Jurado KA, Morrisey EE, Aguilar-Carreno H, Kahn ML: Endothelial SARS-CoV-2 infection is not the underlying cause of COVID-19-associated vascular pathology in mice Front Cardiovasc Med : 2023.

Hoofnagle MH, Hess A, Nalugo M, Ghosh S, Hughes SW, Fuchs A, Welsh JD, Kahn ML, Bochicchio GV, Randolph GJ, Leonard JM, Turnbull IR: Defects in vein valve PROX1/FOXC2 antithrombotic pathway in endothelial cells drive the hypercoagulable state induced by trauma and critical illness J Trauma Acute Care Surg : 2023.

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Academic Contact Information

11-123 Smilow Center for Translational Research
3400 Civic Center Boulevard, Bldg. 421
Philadelphia, PA 19104-5159
Phone: 215-898-9007