Melissa Colbert, PhD
Appointment
Research Assistant Professor
Email
melissa.colbert@chmcc.org
Phone
513-636-7057
Fax
513-636-8966
Credentials
BA: SUNY New Paltz, New Paltz NY, 1979
MS: University of Vermont, Burlington, VT, 1981
PhD: University of Rochester, Rochester, NY, 1990
Fellowship: Post-Doctoral, Duke University Medical Center, Durham, NC. 1994
Research
Dr. Colbert's research focuses on various aspects of heart development and signaling systems that may be associated with cardiac defects. There are three main areas of research:
Retinoic acid actions on the cardiac neural crest
Retinoic acid (RA) is absolutely required for the normal development of the cardiovascular system but it is also a potent cardioteratogen. Most of the common cardiovascular malformations encountered by the clinical cardiologist can be mimiced in animals models by RA. With the increased use of synthetic retinoids to treat a variety of diseases, the dangers of RA exposure during pregnancy and its effects on the developing fetus are of increasing importance. We are particularly interested in the neural crest as a target for the action of RA. The laboratory uses embryos to investigate the sensitivity of neural crest cells to RA, both in vivo and in vitro. In addition, we are currently making quail-to-chick chimeras in collaboration with Dr. Margaret Kirby at the Medical College of Georgia. This will allow us to follow the behavior of RA-treated quail cells in chick hosts. These studies will aid in determine the timing of sensitivity, the biological consequences and the targets of RA action in the neural crest.
The role of parathyroid hormone related peptide (PTHrP) in cardiovascular development
Overexpression of both PTHrP and receptor, PTHrP-R, in the heart is embryonic lethal. Hearts from 9.5 days post coitum (dpc) embryos show a failure of the trabecular myocardium to develop and signs of heart failure. Very little is known about the early expression pattern of PTHrP and PTHrP-R in the embryonic heart. Gene targeted animals that survive to term have no cardiac phenotype, however, a significant number of embryos die in utero about 9.5 days post coitum. Preliminary evidence suggests that the heart may be effected however, this lethal phenotype has not been fully described. We propose to analyze where and when the native ligand and receptor are expressed in wild type embryos using in situ hypridization and immmunohistochemistry, to characterize the lethal phenotype in the global PTHrP knock out animals, and to determine whether PTHrP/PTHrP-R affect myocardial cell proliferation rates in the combined overexpressers. ?-myosin heavy chain mice that drive expression of cre recombinase will be mated with mice that harbor loxP PTHrP and PTHrP-R genes. This will allow us to specifically determine whether loss of either ligand or receptor critically affects cardiac development. Since overexpression has been shown to phenocopy tissue-specific knock out results in every other tissue where PTHrP/PTHrP-R are expressed, it is highly likely that this ligand and it receptor have a critical heretofor unrecognized function during heart development. These studies are in collaboration with Dr. Thomas Clemens at the University of Cincinnati.
Analysis of early development of the cardiac conduction system
This area involves the development of specialized promoters that will regulate transgene expression in the developing mouse cardiac conduction system. We are currently analyzing the expression patterns of transgenes controlled by the ? myosin heavy chain promoter that contains either of 2 mutations in regulatory sequences. These specialized contructs will allow us to manipulate ion channel composition or gap junctional communication within the conduction system and create models of congenital arrhythmias.
Publications, Most Recent
Colbert, M.C.; Hall, D.G.; Kimball, T.R.; Witt, S. A.; Lorenz, J.N.; Hewett, T.E.; Klivitsky, R; Robbins, J. (1997) Cardiac compartment specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive herat failure in transgenic mice,.Journal of Clinical Investigation, 1997; 100: 1958-1968.
Sun, W.Y; Witte, D.P.; Degan, J.L.; Colbert, M.C.; Burkhart, M.; Holmbeck, K.; Xia, Q.; Bugge, T.; Degan, S.J.F.: Prothrobin deficiency results in partial embryonic lethality in mice.Procedings of the National Acadamy of Science, USA 1998; 95: 7597-7602.
Sussman, M.A.; Lim, H.W.; Cambon, N.; Taigen, T.; Olson, E.N.; Robbins, J.; Colbert, M.C.; Wieczorek, D.F.; Molkentin, J.D. Prevention of cardiac hypertrophy in mice by calcineurin inhibition.Science, 1998; 281: 1690-1693.
Qian, J.; Lorenz, J.N.; Maeda, S.; Sutliff, R.L.;Weber, C.; Nakayama, T.; Colbert, M.C.; Paul, R.J.; Fagin, J.A.; Clemens, T.L. Reduced blood pressure and increased sensitivity of the vasculature to PTHrP intransgenic mice overexpressing the PTH/PTHrP- related protein receptor in vascular smooth muscle.Endocrinology, 1999;140:1826-1833.
Muraoka, R.S.; Sun. W.Y.; Colbert, M.C.; Waltz, S.E.; Witte, D.P.; Degen, J.L.; Degen, S.J.F. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse.Journal of Clinical Investigation, 1999;103: 1277-1285.
Professional Organization Memberships
- Member and Co-Chairman of Peer Review Committee 5B; American Heart Association Southern Research Consortium, 1996-1999
- American Association of Anatomists, 1996-1999
- Society for Developmental Biology, 1997-1999
Personal Statement
Research Description
My research focuses on neural crest and its role in heart development.
The neural crest is a unique population of embryonic cells. They have the potential to migrate to many different sites throughout the developing embryo and contribute cells to a variety of different organs and tissues. One of these target tissues is the heart. There the neural crest provides cells that separate the single outflow vessel into the aorta and pulmonary artery. Many children are born with cardiac defects related to the failure of these cells to reach the heart.
In my research, we use retinoic acid, a derivative of vitamin A, to study neural crest behavior. Neural crest cells are very sensitive to changes in retinoic levels. Too much or too little is harmful and will alter their ability to migrate and multiply normally. This system serves as a model in which to examine the mechanisms important in the normal behavior of neural crest and how they altered by drugs or mutations. Through an understanding of these interactions, we will have a better opportunity for counseling and prevention of neural crest-related heart defects.
Related Areas
This person works in these other areas at Cincinnati Children's Hospital Medical Center:
