Research

We investigate signaling pathways that regulate cardiovascular development and function. The cardiovascular system is composed of the heart, blood, blood vessels and lymphatic vessels. We address questions and pathways in all of these cardiovascular components because of the important interactions between them. Our in vivo approaches include mouse and fish genetics to investigate signaling pathways during cardiovascular development and in adult animals. Our in vitro approaches include biochemistry and cell biology, often with specialized systems such as flow chambers to reproduce the fluid shear forces of blood flow, and through collaborative efforts for more specialized studies such as protein structure.

Major areas of investigation in our lab include:

• • Mechanisms of blood vessel development: the CCM pathway
• • Mechanisms of blood vessel development: Klf2 and fluid shear
• • Mechanisms of lymphatic vascular development: SLP76 and vascular separation
• • Mechanisms of hemostasis: platelet collagen receptor signaling
  
  

Mechanisms of blood vessel development: the CCM pathway

Cerebral cavernous malformations (CCMs) are common, familial vascular malformations that cause strokes and seizures. Positional cloning studies have identified mutations in three novel proteins, CCM1, CCM2 and CCM3, which interact biochemically but have no defined function. Convergent studies in zebrafish have shown that mutations in a novel cell surface receptor Heart of Glass (Heg), zCCM1, or zCCM2 give rise to a dilated heart during embryonic development. We have recently used studies of fish and genetically modified mice to demonstrate that this novel signaling pathway regulates cardiovascular development and causes human vascular disease through control of endothelial cell junctions (Kleaveland et. al. Nature Medicine 2009). Studies are ongoing to understand how this pathway regulates endothelial cell function through molecular and genetic dissection of upstream inputs and downstream effectors.

Mechanisms of blood vessel development: Klf2 and fluid shear

The endothelial cells lining blood vessels are exposed to varying levels of fluid shear forces as blood is pumped through the body by the beating heart. Physiologic studies have revealed vascular responses to fluid shear such as regulation of blood pressure and risk of atherosclerosis, but the molecular mechanisms by which this physical force is sensed and transduced to genetic responses are not well understood. We have shown that the transcription factor Klf2 is required in endothelial cells to regulate vascular tone in response to fluid shear during mouse development (Lee et al Developmental Cell 2006) and that Klf2 also regulates the movement of T cells when they exit the thymus (Sebzda et al Nature Immunology 2008). How Klf2 is activated by fluid shear, its role in the cardiovascular system of the mature animal, and Klf2’s downstream molecular targets are being studied in the lab.

Mechanisms of lymphatic vascular development: SLP76 and vascular separation

Shortly after formation of the heart and blood vessels, mammals develop lymphatic vessels to absorb excess interstitial fluid, transport intestinal fats, and coordinate immune cell movement through the body. Lymphatics also provide a primary means of metastasis for human cancers. We have shown that lymphatic vessel separation from blood vessels requires signaling by the immune receptor pathway in blood cells, including the Syk kinase and SLP76 adaptor (Abtahian et al Science 2003). Genetic rescue studies and bone marrow transplantation studies have demonstrated that this pathway is required in a subset of blood cells (Sebzda et al Developmental Cell 2006). We are using molecular and genetic clues to determine how blood cells regulate lymphatic endothelial cell function and are working to develop new mouse genetic tools to investigate signaling pathways in lymphatic endothelial cells.

Platelet signaling during hemostasis

Blood vessel injury would result in fatal bleeding if not for mechanisms of hemostasis. Mammals utilize platelets, specialized anuclear cells, to recognize and plug sites of vessel injury. Platelet collagen responses are a primary hemostatic response that is mediated by two structurally distinct receptors, the immune-type receptor glycoprotein VI and the integrin a2b1. We have found that both of these receptors are necessary for platelets to respond to collagen (Chen et al Molecular and Cellular Biology 2003 and Chen et al Genes and Development 2006). The contribution of each of these receptors and their coordinated signaling mechanism is the focus of ongoing studies in the lab.

 

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People / Lab Members

Mark Kahn, MD, Associate Professor, 215-898-9007, markkahn@mail.med.upenn.edu

Patricia Mericko, Lab Manager, 215-573-7069, pmericko@mail.med.upenn.edu

Cara Bertozzi, 215-573-1191, bertozzi@mail.med.upenn.edu

Chiu-Yu Chen, 215-573-1191, chiuyu.chen@gmail.com

Mei Chen, 215-573-7142, chenmei@mail.med.upenn.edu

Ben Kleaveland, 215-573-7142, kleavela@mail.med.upenn.edu

John Lee, 215-573-1191, john.lee@uphs.upenn.edu

Alec Schmaier, 215-573-1191, schmaier@mail.med.upenn.edu

Xiangjian Zheng, 215-573-7142, zhengx2@mail.med.upenn.edu

Zhiying Zou, 215-898-7311, zzou@mail.med.upenn.edu

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Publications

To see more of Dr. Kahn's publications, please visit

Kleaveland B, Zheng X, Liu JJ, Blum Y, Tung JJ, Zou Z, Chen M, Guo L, Zhou D, Kitajewski J, Affolter M, Ginsberg MH, Kahn ML. Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway. Nature Medicine. 2009 Feb;15(2):169-76.

Sebzda E, Zou Z, Lee JS, Wang T, Kahn ML. Klf2 regulates naive T cell migration by restricting chemokine receptor expression patterns. Nature Immunology. 2008 9(3):292-300.

Lee JS, Yu Q, Shin JT, Sebzda E, Bertozzi C, Chen M, Mericko P, Stadtfeld M, Zhou D, Cheng L, Graf T, MacRae CA, Lepore JJ, Lo CW, Kahn ML. (2006) Klf2 is an essential regulator of vascular hemodynamic forces in vivo. Developmental Cell. 2006 Dec.11 (6):845-57.

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 Sep; 11(3):349-61.

Chen H, Zou Z, Sarratt KL, Zhou D, Lu MM, Hammer DA, Kahn ML. In vivo integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines. Genes and Development, 2006 Apr 15;20(8):927-32.

Sarratt, KL, Chen, H, Zutter, MM, Santoro, SA, Hammer, DA, Kahn, ML. GPVI and a2b1 play independent critical roles during platelet adhesion and aggregate formation to collagen under flow. Blood. 2005 Aug 15;106(4):1268-77.

Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsia A, Myers EE, Huang B, Jackson DG, Ferrari VA, Tybulewicz V, Lowell CA, Lepore JJ, Joretzky GA, Kahn ML. (2003). Regulation of blood lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299(5604): 247-251.

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Positions

We have open positions for talented and creative individuals at both the postdoctoral and predoctoral levels. Please email inquiries with a cover letter, CV and the names of three references.

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Contact Information

Mark L. Kahn, MD
Associate Professor, University of Pennsylvania
952 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104-6069

Office: 215-898-9007
Fax: 215-573-2094
Email: markkahn@mail.med.upenn.edu

Patricia Mericko, Lab Manager
937 BRB II/III
421 Curie Blvd.
Philadelphia, PA 19104-6069

Phone: 215-573-7069
Fax: 215-573-2094
Email: pmericko@mail.med.upenn.edu

Nina Maschak, Administrative Coordinator
Phone: 215-573-8002
Email: maschak@mail.med.upenn.edu

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