Connolly Laboratory Home Page

Research Interests:
Vascular Signal Transduction

Our laboratory is interested in signal transduction by cell surface receptors in the setting of vascular disease. Vascular cells, such as endothelial cells, platelets, and vascular smooth muscle cells, are positioned at the interface between blood and other tissues, putting them in the unique position of sensing a vast number of different stimuli. It is clear that this signal transduction is critical in vascular pathology, including atherosclerosis, arterial stenosis, and thrombosis. By studying the molecular mechanisms of this signal transduction, we hope to identify good therapeutic targets for the treatment of vascular disease.

Our current studies focus on the responses of vascular cells to the products of thrombosis and hemostasis, including thrombin and ADP. Thrombin is generated during coagulation and is a potent stimulus for platelets, endothelial cells, and vascular smooth muscle cells. We have cloned three receptors for thrombin that mediate cellular activation and are currently using mouse knockouts to define their relative tissue-specific roles. In particular, endothelial cells use two of these receptors to confer thrombin-sensitivity and we are working out the relative roles of these receptors in vivo.

The adenine nucleotides, ADP and ATP, are released at high concentrations in the vasculature by platelet secretion, cell lysis, and sympathetic nerve terminal release. These nucleotides stimulate responses in vascular cells through a variety of purinergic receptors of the P2Y and P2X families. In general, the direct effects of nucleotides on platelet aggregation and vasoconstriction are balanced by nucleotide-stimulated antithrombotic and vasodilatory effects mediated by endothelium. This balance is upset in vascular pathologies underlying stroke and myocardial infarction. We are using a variety of approaches, including molecular biology, tissue culture signaling assays, and knockout mice, to examine the functions of three important vascular purinergic receptors in responses to adenine nucleotides: P2X1, P2Y1, and P2T-AC.

Biosketch:

Andrew Connolly joined the Vascular Research Division and Department of Pathology in July 1997. He received his B.A. in Chemistry from Princeton University, his M.D. from Harvard Medical School, and his Ph.D. in Biomedical Sciences from the University of California, San Francisco. At UCSF he completed an Anatomic Pathology residency and Surgical Pathology Fellowship, with a particular interest in Cardiovascular Pathology.

Selected Publications

Lab Personnel:

Mandy Zervoglos, B.S. (mzervoglos@rics.bwh.harvard.edu)

Xiao-Mei Yu, Ph.D. (xyu@rics.bwh.harvard.edu)

Jessica DeFrances, B.S. (jdefrances@rics.bwh.harvard.edu)

Catherine Leon, Ph.D., visiting scientist from Strasbourg (cleon@rics.bwh.harvard.edu)

[Post-doctoral and technician positions are available]

Links:

Vascular Research Division HomePage

Harvard Medical School HomePage

HMS Division of Medical Sciences Graduate Programs

Brigham & Women's Hospital Research

Brigham & Women's Hospital HomePage

"BiologyWeek" listing of seminars in Boston

Yahoo Map/Directions

Harvard Medical School Maps/Directions

Guide to Boston

G Protein-Coupled Receptor Database

Research Interests:

Vascular Signal Transduction

Our laboratory is interested in signal transduction by cell surface receptors in the setting of vascular disease. Vascular cells, such as endothelial cells, platelets, and vascular smooth muscle cells, are positioned at the interface between blood and other tissues, putting them in the unique position of sensing a vast number of different stimuli. It is clear that this signal transduction is critical in vascular pathology, including atherosclerosis, arterial stenosis, and thrombosis. By studying the molecular mechanisms of this signal transduction, we hope to identify good therapeutic targets for the treatment of vascular disease.

Our current studies focus on the responses of vascular cells to the products of thrombosis and hemostasis, including thrombin and ADP. Thrombin is generated during coagulation and is a potent stimulus for platelets, endothelial cells, and vascular smooth muscle cells. We have cloned three receptors for thrombin that mediate cellular activation and are currently using mouse knockouts to define their relative tissue-specific roles. In particular, endothelial cells use two of these receptors to confer thrombin-sensitivity and we are working out the relative roles of these receptors in vivo.

The adenine nucleotides, ADP and ATP, are released at high concentrations in the vasculature by platelet secretion, cell lysis, and sympathetic nerve terminal release. These nucleotides stimulate responses in vascular cells through a variety of purinergic receptors of the P2Y and P2X families. In general, the direct effects of nucleotides on platelet aggregation and vasoconstriction are balanced by nucleotide-stimulated antithrombotic and vasodilatory effects mediated by endothelium. This balance is upset in vascular pathologies underlying stroke and myocardial infarction. We are using a variety of approaches, including molecular biology, tissue culture signaling assays, and knockout mice, to examine the functions of three important vascular purinergic receptors in responses to adenine nucleotides: P2X1, P2Y1, and P2T-AC.

Andrew Connolly joined the Vascular Research Division and Department of Pathology in July 1997. He received his B.A. in Chemistry from Princeton University, his M.D. from Harvard Medical School, and his Ph.D. in Biomedical Sciences from the University of California, San Francisco. At UCSF he completed an Anatomic Pathology residency and Surgical Pathology Fellowship, with a particular interest in Cardiovascular Pathology.