Mission Statement

Our mission is to improve the treatments available for patients suffering from cardiovascular disease by combining basic research aimed at understanding the molecular mechanisms of heart disease with the discovery of innovative small molecule and cell-based therapeutics.

Projects

• Enhance the applicability of stem cells in regenerative medicine.   
• Investigate the stem cell niche and the role it plays in tissue regeneration.
• Define the role integrins and chemokine receptors play in normal heart physiology as well as cardiovascular disease.
• Characterize lipoproteins that are linked to metabolic syndrome and heart disease.
• Develop small molecule therapeutics for the treatment of heart disease.

Spotlight on Current Research THI's Lei Zhou, MD, PhD, was named one of 5 finalists for the prestigious Cournand and Comroe Young Investigator Prize at the 2011 American Heart Association scientific sessions. The purpose of the prize is to encourage promising investigators to continue with their research in biomedical sciences. Zhou presented his work on the use of cell-based prostacyclin gene therapy for the treatment of pulmonary arterial hypertension (PAH), a progressive disorder characterized by abnormally high blood pressure in the arteries of the lungs, which overloads the right side of the heart and causes death. The prognosis for PAH is similar to cancers; the median survival is less than 3 years. Intravenous administration of prostacyclin (a substance naturally produced in the body) is the only treatment option that has demonstrated increased survival rates of PAH patients. However, the treatment has limitations of a short half-life, the placement of a permanent intravenous catheter, and side effects associated with systemic delivery. By using bone marrow-derived, cell-based prostacyclin gene therapy in an animal PAH disease model, Zhou and his team in the Wafic Said Molecular Cardiology Research Lab at THI (Director, Dr. Richard Dixon) proved that this new treatment method can prevent the development of PAH, increase the survival rate of manifested PAH, and help overcome the delivery limitations. Research has shown that a one-time delivery of the engineered cells offered survival benefit for at least 4 weeks, which may make it a promising option for PAH patients. "THI is very proud of this work and of the dedication of Lei Zhou and his colleagues in the lab," said THI President and Medical Director James T. Willerson, MD.

Definitions

What is a stem cell?

A stem cell is a unique cell that can proliferate and differentiate into other cell types with specialized functions such as those of muscle, brain, blood or skin. In adults, they contribute to the repair of damaged tissue by regenerating those cell types necessary for proper organ function.

What is the stem cell niche?

The stem cell niche is the microenvironment in which the stem cells reside. The niche supports the maintenance of stem cell identity and regulates the function of stem cells.

What is an integrin?

The integrins are a family of proteins present on the surface of all cells that are critical for cell movement, growth, and adherence. During an immune response, integrins mediate white blood cell trafficking to sites of inflammation. In a similar fashion, integrins are required for stem cell localization in bone marrow and the subsequent trafficking of these cells to sites of tissue damage.

What is a cell-based versus a small molecule therapeutic?

Cell-based therapies involve the injection of cells into a patient to replace those damaged by disease. Typically, these cells are isolated from a donor (in some cases, the patient) and manipulated in some fashion prior to injection. In contrast, small molecules are low molecular weight drugs chemically synthesized in the laboratory. They are typically administered orally, intravenously, or locally and act on the patient’s own cells. Such drugs are typically optimized for potency, selectivity, bioavailability and side-effect profile.

Principal Investigators and Key Personnel

• Richard A. F. Dixon, PhD* – Director MCRL
• Chu-Huang (Mendel ) Chen, MD, PhD* – Director Vascular & Medicinal  Research
• Ronald J. Biediger, PhD* – Associate Director Chemistry MCRL
• Peter Vanderslice, PhD* – Associate Director Biology  MCRL
• Darren G. Woodside, PhD* – Assistant Director MCRL
• Mehran Haidari, PhD – Sr Research Scientist MCRL
• Qi Liu, PhD – Research Scientist MCRL
• Xuhai  (Jonathan) Lu, PhD – Research Scientist Vascular & Medicinal  Research
• Deenadayalan Bakthavatsalam, PhD – Research Associate MCRL
• Lei Zhou, MD, PhD – Research Associate MCRL
• Matthew Robertson, PhD – Research Associate MCRL
• Jianwen (Jane) Dong, PhD – Research Fellow Vascular & Medicinal  Research
• Amy R. Caivano – Research Associate MCRL
• C. William Gundlach* – Research Associate MCRL
• Anna Kazansky – Research Associate MCRL
• Sayadeth Khounlo - Research Associate MCRL
• Robert V. Market – Research Associate MCRL
• Su Pan, MD – Research Associate MCRL
• Michael M. Savage – Research Associate MCRL
• Sidney Sherwood – Research Associate MCRL
• Navin D. Warier – Research Associate MCRL
• Zhenping Chen – Sr Research Assistant MCRL
• Toya J. Terry – Sr Research Assistant  MCRL
• Wei Zhang – Sr Research Assisant MCRL

* For THI professional staff member profiles, see Research. 

Contact Information

Richard A. F. Dixon, PhD

For More Information

Research Director Awarded Recovery Act Grant from National Heart, Lung and Blood Institute. News release, January 15, 2010.

Texas Heart Institute at St. Luke's Episcopal Hospital Appoints New Research Director . (PDF)
Texas Heart Institute Update. 2008; Issue 2:17.

Researchers Study the Roles of Integrins and Chemokines in Stem Cell Mobilization, Homing, and Engraftment. (PDF)
Heart Watch. 2009; Winter: 4.

Selected Publications

Gundlach CW, Caivano A, Cabreira-Hansen MD, Gahremanpour A, Brown WS, Zheng Y, McIntyre B, Willerson JT, Dixon RA, Perin EC, Woodside D. Synthesis and Evaluation of an Anti-MLC1 x Anti-CD90 Bispecific Antibody for Targeting and Retaining Bone-Marrow Derived Multipotent Stromal Cells in Infarcted Myocardium. Bioconjug Chem.2011;in press.

Terry T, Chen Z, Dixon RA, Vanderslice P, Zoldhelyi P, Willerson JT, Liu Q. CD34/M-cadherin Bone Marrow Progenitor Cells Promote Arteriogenesis in Ischemic Hindlimbs of ApoE Mice. PLoS ONE.2011;6(6):e20673.

Haidari M, Zhang W, Ganjehei L, Ali M, Chen Z. Inhibition of MLC Phosphorylation Restricts Replication of Influenza Virus-A Mechanism of Action for Anti-Influenza Agents. PLoS ONE.2011;6(6):e21444.

Ruan CH, Dixon RA, Willerson JT, Ruan KH. Prostacyclin therapy for pulmonary arterial hypertension. Tex Heart Inst J.2010;37(4):391-399.

Vanderslice P, Woodside DG, Caivano AR, Decker ER, Munsch CL, Sherwood SJ, Lejeune WS, Miyamoto YJ, McIntyre BW, Tilton RG, Dixon RA. Potent in vivo suppression of inflammation by selectively targeting the high affinity conformation of integrin alpha4beta1. Biochem Biophys Res Commun. 2010;400(4):619-624.

Haidari M, Wyde PR, Litovsky S, Vela D, Ali M, Casscells SW, Madjid M. Influenza virus directly infects, inflames, and resides in the arteries of atherosclerotic and normal mice. Atherosclerosis.2010;208(1):90-96.

Chen CH, Dixon RAF, Ke LY, Willerson JT. Vascular progenitor cells in diabetes mellitus: roles of Wnt signaling and negatively charged LDL. Circ Res 2009;104:1038-40.

Liu Q, Chen Z, Terry T, McNatt JM, Willerson JT, Zoldhelyi P. Intra-arterial transplantation of adult bone marrow cells restores blood flow and regenerates skeletal muscle in ischemic limbs. Vasc Endovascular Surg. 2009;43(5):433-443.

Lu J, Jiang W, Yang JH, Chang PY, Walterscheid JP, Chen HH, Marcelli M, Tang D, Lee YT, Liao WS, Yang CY, Chen CH. Electronegative LDL impairs vascular endothelial cell integrity in diabetes by disrupting fibroblast growth factor 2 (FGF2) autoregulation. Diabetes. 2008;57(1):158-166.

Tang D, Lu J, Walterscheid JP, Chen HH, Engler DA, Sawamura T, Chang PY, Safi HJ, Yang CY, Chen CH. Electronegative LDL circulating in smokers impairs endothelial progenitor cell differentiation by inhibiting Akt phosphorylation via LOX-1. J Lipid Res. 2008;49(1):33-47. 

Woodside, D.G. and Vanderslice P.  Cell Adhesion Antagonists: Therapeutic Potential in Asthma and COPD. BioDrugs. 2008;22(2):85-100.

Vanderslice, P. andWoodside D.G. Integrin antagonists as therapeutics for inflammatory diseases. Expert Opin Investig Drugs. 2006;15(10):1235-55.

D. Woodside, R.M. Kram, J.S. Mitchell, T. Belsom, M.J. Billiard, B.W. McIntyre, and P. Vanderslice.  Contrasting Roles for Domain 4 of VCAM-1: A negative regulator of soluble binding, but a mediator of firm adhesion as an immobilized substrate. J Immunol. 2006; 176(8):5041-9.

Liu Q, Chen ZQ, Bobustuc GC, McNatt JM, Segall H, Pan S, Willerson JT, Zoldhelyi P.  Local gene transduction of cyclooxygenase-1 increases blood flow in injured atherosclerotic rabbit arteries. Circulation. 2005;111:1833-40.

Biediger, R. J.; Chen, Q.; Decker, E. R.; Holland, G. W.; Kassir, J. M.; Li, W.; Market, R. V.; Scott, I. L.; Wu, C.; Li, J. “Carboxylic Acid Derivatives that Inhibit the Binding of Integrins to Their Receptors” U. S. Patent No. 6,972,296.  December 6, 2005.

Biediger, R. J.; Dupre, B.; Hamaker, L. K.; Holland, G. W.; Kassir, J. M.; Li, W.; Market, R. V.; Nguyen, N.; Scott, I. L.; Wu, C.; Decker, E. R. “Propanoic Acid Derivatives that Inhibit the Binding of Integrins to Their Receptors” U. S. Patent No. 6,723,711.  April 20, 2004

Vanderslice P, Biediger RJ, Woodside DG, Berens KL, Holland GW, Dixon RA. Development of cell adhesion molecule antagonists as therapeutics for asthma and COPD. Pulm Pharmacol Ther. 2004;17(1):1-10.

Langer R, Wang M, Stepkowski SM, Hancock WW, Han R, Li P, Feng L, Kirken RA, Berens KL, Dupre B, Podder H, Dixon RA, Kahan BD. Selectin inhibitor bimosiamose prolongs survival of kidney allografts by reduction in intragraft production of cytokines and chemokines. J Am Soc Nephrol. 2004 Nov;15(11):2893-901

Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR; STRIDE-1 Study Group.  Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004 Feb 15;169(4):441-7

Wu C, Decker ER, Blok N, Bui H, You TJ, Wang J, Bourgoyne AR, Knowles V, Berens KL, Holland GW, Brock TA, Dixon RA.  Discovery, modeling, and human pharmaco-kinetics of N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a second generation, ETA selective, and orally bioavailable endothelin antagonist. J Med Chem. 2004;47(8):1969-86.

Wu C, Holland GW, Brock TA, Dixon RA. Recently discovered sulfonamide-, acyl sulfonamide- and carboxylic acid-based endothelin antagonists. IDrugs. 2003 Mar;6(3):232-9

---

Updated: November 2011