Raymond B. Runyan
Professor, Cell Biology and Anatomy
Associate Research Scientist, Sarver Heart Center
Investigator, Center for Toxicology
Faculty member, Physiological Sciences Program
E-mail: rrunyan@email.arizona.edu
B.A. Macalester College
M.S. Florida State University,
Ph.D., Texas Tech University Health Sciences Center,
Postdoctoral Research- University of Connecticut Health Center
and University of Texas M.D. Anderson Cancer Center
Teaching Areas- Human Gross Anatomy (Embryology), Developmental Biology (Undergraduate), Seminar in Developmental Biology (Graduate)
Assistant Professor and Associate Professor, University of Iowa, 1986-1993.; Member, American Heart Association Review Committee on Lung and Development, 1988-1991.; Established Investigator, American Heart Association, 1991-1996.; R. R. Bensley Award, American Association of Anatomists, 1992.; Editorial Board, Anatomical Record, 1992-1998; Member, NIH Study Section on Human Embryology and Development 2, 1993-1997., Member, Cell Differentiation and Function (CDF-6 Study Section, 2000-2004.
Runyan Lab Gang- Showing recent members of the lab who have moved on.
Lft to Rt.- C. "Hawkeye" Wendler (now at Med. Coll. of Wisc.), Capt. R. Runyan, S. Salek (Med Student- U of A.), W. "Lt." Finch (Med Student- Uniformed Services H.S. University), R. Turner (now at U of Minn.), A. Boyer (now Scientist at Procter & Gamble), A. "Annie Oakley" Pollack. Front Row- L. "Slug" Romano (now at Duke Univ.) and M. "Clones" Collier (now at UCSF)
Research described here has been supported for many years by the National Heart, Lung and Blood Institute of the National Institutes of Health and at times from the American Heart Association. Current Support comes from P01 HL 63926. a Program Project Grant entitled "Commitment and Differentiation of Cardiac Phenotypes", R. Runyan, Program Director. Support for TCE-related toxicology of heart development comes from a superfund research grant to the U of A, J. Gandolfi, Program Director and O. Selmin, Project Leader. Dr. Pollack's suport for research in the laboratory is via a postdoctoral fellowship from the Mountain West Affiliate of the American Heart Association.
Research Interest:
Mechanisms of tissue interaction and cellular transformation in the developing heart
During development, differentiation is regulated by interaction between cells. In the heart, cells that form the valves are induced to develop by interaction between endothelial cells and adjacent muscle. As a result, cardiac endothelial cells transform into mesenchyme and become the constituents of the valves and walls of the heart. Since a large percentage of congenital heart defects involve defects in these structures, an understanding of normal developmental regulation would allow us to identify the developmental process that was mis-regulated. The objective of my research program is to understand the molecular mechanisms that mediate cell transformation in the heart.
Using a tissue culture assay, it was shown that cardiac endothelia would only transform after stimulation by adjacent muscle. My laboratory has continued to examine the events which take place during this epithelial-mesenchymal cell transformation. Our studies focus upon three basic questions. 1) What is the nature of the signal produced by the muscle? 2) How do the target cells recognize the signal? 3) What events occur in the target cells in response to the stimulus? With collaborators at other institutions, we have begun to examine whether some of these molecules might be involved in congenital heart defects.
Work in the laboratory has focused on the observation that the growth factor, Transforming Growth Factor Beta, is a component of the transformation process. As this growth factor is actually a member of a family of related molecules, we used RNase protection assays to show that two isoforms, TGFß2 and TGFß3, were found in the heart. Experiments using antisense DNA oligonucleotides demonstrated that TGFß3 is the critical component. More recently, our work shows that both isoforms are used in complementary roles. Colleagues at another institution expanded on this work to show that mice defective in the TGFß2 isoform have heart defects that look similar to Tetrology of Fallot
Recent experiments showed that transformation in the heart is blocked by antibodies to two different classes of TGFß receptors. Like the two different TGFß isoforms, each receptor appears to mediate separate components of the cell transformation process. One aspect of this story that looks promising is the fact that one of these receptors maps to a region in the human genome associated with congenital heart disease. Studies by a colleague are underway to determine whether this molecule is responsible for an inherited form of atrioventricular canal defect. Other experiments in this laboratory showed that transformation is sensitive to inhibitors of several classes of kinases, Gi proteins, and the phosphoinositide pathway. These pathways are being explored by cloning and targeted degradation of mRNAs of various components in order to track signals from the cell surface to the nucleus.
A third approach to the problem is towards the identification of regulatory genes expressed in response to the cardiac signal. Our focus is the immediate early genes which are likely to be transcriptional regulators of other genes required for valve formation. Our most recent efforts have focused on the genes Slug and Mox-1. Both of these genes appear to be critical for the process of cell transformation
A related research program in the lab is focused upon examining the relationship between events which take place during early valve development and the apparent cardio-teratogenicity of the environmental contaminant Trichloroethylene or TCE. In association with members of the Pediatric Cardiology Division and the Dept. of Pharmacology and Toxicology, we are trying to identify genes that are altered in developing hearts by exposure to this chemical.
Selected Publications:
Huang J-X, JD Potts, EB Vincent, DL Weeks, RB Runyan (1995). Mechanisms of cell transformation in the embryonic heart. Proceed NY Acad Sci 752:317-330.
Brown, CB, AS Boyer, RB Runyan and JV Barnett (1996). Antibodies against the TGFß type II receptor block cell transformation and migration in the embryonic heart. Developmental Biology 174:248-257.
Johnson, PD, BV Dawson, and RB Runyan (1997). Trichloroethylene and its potential as a cardiac teratogen. In "Comprehensive Toxicology Volume 6- Cardiovascular Toxicology". S. Bishop and W. Kerns, eds., Permagon Press, New York. pp. 433-444.
Vincent, EB, RB Runyan and DL Weeks (1998). Production of the transforming growth factor-ß binding protein endoglin is regulated during chick heart development. Developmental Dynamics 213, 237-247.
Pollack, AL, RB Runyan and KE Mostov (1998). Morphogenetic mechanisms of epithelial tubulogenesis: MDCK cell polarity is transiently rearranged without loss of cell-cell contact during scatter factor/hepatocyte growth factor-induced tubulogenesis. Developmental Biology 204, 64-79.
Boyer, AS, CF Erickson, and RB Runyan (1999). Epithelial-mesenchymal transformation in the embryonic heart is mediated through distinct pertussis toxin-sensitive and TGFß signal transduction mechanisms. Developmental Dynamics 214, 81-91.
Boyer, AS, II Ayerinskas, EB Vincent, L McKinney, DL Weeks, and RB Runyan. (1999) TGFß2 and TGFß3 have separate and sequential activities during epithelial-mesenchymal cell transformation in the embryonic heart. Developmental Biology 208, 530-545.
Runyan, RB, CC Wendler, LA Romano, AS Boyer, JM Dagle and DL Weeks (1999) Utilization of antisense oligodeoxynucleotides with embryonic tissues in culture. Methods: A Companion to Methods in Enzymology 18, 316-321.
Brown, CB, AS Boyer, RB Runyan and JV Barnett (1999). Requirement of the type III TGF-ß receptor for endocardial cell transformation in the heart. Science 283, 2080-2082.
Romano, LA and RB Runyan (1999). Slug is a mediator of epithelial-mesenchymal cell transformation in the developing chick heart. Developmental Biology 212, 243-254.
Boyer, AS, WT Finch and RB Runyan (2000). Trichloroethylene inhibits development of embryonic heart valve precursors in vitro. Toxicological Sciences (in press).
Boyer, A.S. and R.B. Runyan (2000). TGFß Signal transductionin the atrioventricular canal during heart development. In "Heart Development" R. Tomanek and R. Runyan, eds, JAI Press. (In press)
J.M. Collier, C.C. Cover, O. Selmin, P.D. Johnson and R.B. Runyan (2000). Trichloroethylene effects on gene expression during cardiac development. Submitted.
J.M. Collier, O. Selmin, and R.B. Runyan (2000). Identification and characterization of p137 as a cardiac marker differentially regulated with trichloroethylene exposure. Submitted.
S.E. Klewer, A.Person, I.N. Jongewaard, H.L. Bartlett and R.B. Runyan (2000). Type VI collagen is a functional element of cardiac endocardial morphogenesis. Submitted.
Graduates from the lab
Jay Potts, Ph.D. , University of South Carolina
Christos Georgiou, Ph.D., M.D., Charing Cross Hospital, University of London
Jian-Xin Huang, Ph.D., M.D, Medical University of South Carolina.
J. Michael Collier, Ph.D., University of California, San Francisco
Laura A. Romano, Ph.D., Duke University
Christopher C. Wendler, Ph.D., Medical College of Wisconsin
The University of Arizona hosted the 1999 Weinstein Cardiovascular Development Conference, May 20-23, 1999
Connect to the 2001 Weinstein Cardiovascular Development Conference Web Site, Dallas, TX., May 17-20, 2001
Other links for heart and embryo development from around the country:
Descriptions of congenital heart disease
Congenital heart disease support page for patients and parents
Information on Congenital Heart Disease
Early embryo development from the Visible Embryo Project at UCSF
A few other cardiac development scientists with web pages
Dr. Schwartz at Baylor
Dr. Doetschman at Cincinnati
The Molecular Cardiology Group at Cincinnati
Dr. Kirby at Medical College of Georgia
Dr. Mikawa at Cornell
Dr. Antin at Arizona
Dr. Barnett at Vanderbilt
Dr. Fishman at Harvard
Dr. Bodmer at Michigan
Dr. Conway at MCG
Dr. Weeks at Iowa
Dr. Stanier at UCSF
Dr. Markwald at MUSC
Dr. Little at MUSC
Dr. Kubalak at MUSC
Dr. Borg at South Carolina
