Cheryl Hillery, M.D.

Investigator
Blood Research Institute
BloodCenter of Wisconsin

Associate Professor
Department of Pediatrics and Medicine
Medical College of Wisconsin

Doctoral Training

M.D., Duke University School of Medicine, 1984
 

Postdoctoral Training

Residency and Fellowship, University of North Carolina, 1991

Selected Publications
Grant Support
Invited Lectures
Laboratory Staff
Contact Information

Research Interests
Sickle cell disease is caused by a genetic disorder of hemoglobin in red blood cells. People with sickle cell disease commonly experience “crises” due to stoppage of flow in their blood vessels, which can result in injury to any of the body's tissues or organ systems. This includes stroke in approximately 20% of children with sickle cell disease. The development of vascular obstruction in sickle cell disease is complicated and likely involves many different abnormalities of both circulating blood and the blood vessel wall. We currently have a poor understanding of how “vaso-occlusive crises” occur. Because of this, there are currently few choices for effective treatment of patients with sickle cell disease.

The sickle red cell is abnormally sticky to the cells and proteins that line the blood vessel wall. Previously, our laboratory has found that two sticky proteins, thrombospondin and laminin, strongly bind to sickle red cells. We have mapped the adhesive site on thrombospondin to the terminal 15% of the protein. We are currently developing reagents that will interfere with how the sickle red cells bind to the vessel wall. Using “phage display” technology, our laboratory has isolated synthetic antibodies that bind either thrombospondin or sickle red cells. These genetically engineered antibodies partially block the stickiness of sickle cells under flow conditions that mimic shear forces in the small blood vessels where vaso-occlusion likely occurs. These synthetic antibodies will be novel reagents to further characterize the sticky sites on sickle cells that may be contributing to vascular obstruction in sickle cell disease. Our laboratory also works with genetically engineered “sickle cell mice” that experience spontaneous sickle cell disease-like complications such as vaso-occlusive crises and stroke. In collaboration with Dr. Hudetz at the Medical College of Wisconsin, we have found that these mice also have sticky sickle red cells that abnormally bind to the blood vessel walls within their brains. 

The clotting system is abnormally activated in patients with sickle cell disease. Fibrin and tissue factor are clotting proteins that are substantially increased in patients with sickle cell disease. Our laboratory has found increased levels of fibrin deposited in the organs of sickle mice that are affected by vascular obstruction, suggesting that clotting is an important part of the organ damage. We are now combining sickle cell disease with mice deficient in factors that are important for blood clotting: tissue factor and fibrinogen. We have found that sickle mice missing fibrinogen have less sites of tissue damage within some of their organs. These models of sickle cell disease merged with specific genetic defects in the blood-clotting pathway should provide evidence as to exact the role of the clotting system in the evolution of vaso-occlusion. If clotting is important, then anticoagulation therapy may be beneficial to prevent organ damage in patients with sickle cell disease.

The blood vessel wall is also injured in sickle cell disease. Sickle mouse blood vessels cannot relax normally and have oxidative injury, similar to arteries in people with atherosclerosis (heart disease). We have shown that the development of stroke and lung damage in sickle mice may be in part due to abnormalities of the nitric oxide pathway, an important regulator of blood vessel relaxation. In collaboration with Dr. Pritchard’s laboratory, we have also found that treating sickle mice with agents that improve oxidative vessel wall injury, improves the ability to relax sickle mouse blood vessels.

In summary, we propose that the combination of the abnormal stickiness of the sickle red cell, the over-activity of the blood clotting system, and vessel wall damage contribute importantly to blood vessel occlusion and crises in sickle cell disease. Our work should provide a better understanding of the complex interactions between red blood cells, clotting proteins and the injured vessel wall in the development of sickle cell vaso-occlusion. We hope that a better understanding of these different disease processes will result in improved therapy for patients who suffer from sickle cell disease.

Selected Publications

• C.A. Hillery, M.C. Du, R.R. Montgomery, and J.P. Scott (1996) Increased adhesion of erythrocytes to components of the extracellular matrix: Isolation and characterization of a red blood cell lipid that binds thrombospondin and laminin. Blood 87:4879-4886.
• J.A. French, D. Kinney, J.P. Scott, R.G. Hoffmann, J.D. Wood, A.G. Hudetz, and C.A. Hillery (1997) Mechanisms of stroke in sickle cell disease: role of the nitric oxide pathway in a rat cerebral microvascular model Blood 89:4591-4599.
• C.A. Hillery (1998) Potential therapeutic approaches for the treatment of vaso-occlusion in sickle cell disease. Current Opinion in Hematology 5:151-155.
• C.A. Hillery, M.C. Du and J.P. Scott (1999) The carboxy-terminal cell binding domain of thrombospondin is essential for sickle red blood cell adhesion. Blood 94:302-309.
• C.A. Hillery, M.C. Du, W.C. Wang and J.P. Scott (2000) Hydroxyurea therapy decreases red blood cell adhesion to thrombospondin and laminin in sickle cell disease. British Journal of Haematology 109:322-327.
• C.A. Hillery (2002) Adhesion of sickle erythrocytes to extracellular matrix. Interactions of Blood and the Pulmonary Circulation. E.K. Weir, H.L. Reeve and J.T. Reeves (eds). Futura Publishing Company, Inc; Armonk, NY pp69-82.
• N.A. Watkins, L.M. Du, J.P. Scott, W.H. Ouwehand and C.A. Hillery (2003) Single chain antibody fragments derived from a human synthetic phage display library bind thrombospondin and inhibit sickle cell adhesion. Blood 102:718-724.
• J. Ou, Z. Ou, D.W. Jones, S. Holzhauer, O.A. Hatoum, A.W. Ackerman, D.W. Weihrauch, D.D. Gutterman, K. Guice, K.T. Oldham, C.A. Hillery,* and K.A. Pritchard, Jr.* (2003) L-4F, an apo A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease. Circulation 107:2337-41.
• Y. Saunthararajah, C.A. Hillery, D. Lavelle, R. Molokie, L. Dorn, L. Bressler, S. Gavazova, Y.H. Chen, R. Hoffman, J. DeSimone (2003) Effects of 5-aza-2’-deoxycytidine on fetal hemoglobin levels, red-cell adhesion and hematopoietic differentiation in patients with sickle cell disease Blood 102:358-3664.
• N.J. Wandersee, S.C. Olson, S.L. Holhzaur, R.G. Hoffmann, J.E. Barker and C.A. Hillery (2004) Increased erythrocyte adhesion in mice and humans with hereditary spherocytosis and hereditary elliptocytosis Blood 103:710-716.
• K.A. Pritchard, Jr., J. Ou, Z. Ou, Y. Shi, J.P. Franciosi, P. Signorino, S. Kaul,. C. Ackland-Burglund, K. Witte, S. Holzhauer, N. Mohandas, K. Guice, K.T. Oldham and C.A. Hillery (2003) Hypoxia-induced acute lung injury in murine models of sickle cell disease. Am. J. Physiol:Lung Cellular and Molecular Physiology 286:L705-L714.
• C.A. Hillery and J.A Panepinto (2004) Pathophysiology of stroke in sickle cell disease. Microcirculation 11:195-208.
• J.A. Panepinto, D.C. Brousseau, C.A. Hillery, J.P. Scott (2005). Variation in hospitalizations and hospital length of stay in children with vaso-occlusive crises in sickle cell disease. Pediatric Blood Cancer 44:182-6.
• N.J. Wandersee, R.C. Punzalan, M.P. Rettig, M.D. Kennedy, N.M. Pajewski, R.L. Sabina, J. Paul Scott, P.S. Low, C.A. Hillery (2005). Erythrocyte adhesion is modified by alterations in cellular tonicity and volume. Br J Haematol 131:366-77.
• E.A. Manci, C.A. Hillery, C.A. Bodian, Z.G. Zhang, G.A. Lutty, B.S. Coller (2006). Pathology of "Berkeley" sickle cell mice: similarities and differences with human sickle cell disease. Blood 107:1651-1658.

Grant Support

• NIH: R01 “Red blood cell adhesion in sickle cell disease” (2002 to 2006).
• NIH: PPG Project 4 "Mechanisms of vaso-occlusion in sickle cell disease: role of thrombosis" (2000 to 2005).
• NIH: R01 "Mechanisms of vaso-oclusion in sickle cell disease" (2005-10)

Invited Lectures

• “Adhesion of erythrocytes to extracellular matrix” – American Heart Association Scientific Conference on Interactions of Blood and the Pulmonary Circulation, Sedalia, Colorado (9/7/00).
• “Mechanisms of vaso-occlusion in sickle cell disease” – Emory School of Medicine, Atlanta, GA (8/15/2003).
• “Sickle cell disease: insights into the pathophysiology of vaso-occlusion” – New York Blood Center, New York (10/22/2003).
• “Sickle cell disease: insights into the pathophysiology of vaso-occlusion” – Purdue, LaFayette, IN (1/30/2004).
• “Role of coagulation and inflammatory pathways in sickle cell vasculopathy” – Hemostasis Gordon Research Conference, Colby College, Waterville, ME (7/17/2004)
• "Sickle cell disease: Insights into the pathophysiology of vaso-occlusion" - Children's Hospital of Philadelphia, University of Pennsylvania (1/18/2005)

Back row: Kim Rennie, Sandy Holzhauer, Cheryl Hillery, Tom Foster, Anne Frei
Front row: Teresa Uy, Terri Besch, Andrea French, Dawn Retherford, Nancy Wandersee

Laboratory Staff 

 
Employment Opportunities
If opportunities are available, they will be listed on the Employment page.

Contact Information
Phone: (414) 937-3896
Fax: (414) 937-6284
E-mail: cheryl.hillery@bcw.edu