Biochemistry
R. Bentley
J. Brodsky
J. Franzen
P. Grabowski
J. Hempel
L. Jen-Jacobson
K. Kiselyov
C. Peebles
J. Rosenberg
A. Schwacha

Cell Biology
J. Brodsky
A. Chung
J. Hildebrand
L. Jacobson
N. Kaufmann
K. Kiselyov
J. Pipas
M.-T. Sáens-Robles
W. Saunders
C. Walsh

Computational Biology
M. Grabe
J. Lawrence
J. Rosenberg

Developmental Biology
G. Campbell
D. Chapman
J. Hildebrand
B. Roman
S. Shostak
B. Stronach
V. Twombly

Ecology
T.-L. Ashman
W. Carson
W. Coffman
S. Kalisz
T. Katzner
R. Relyea
S. Tonsor
B. Traw

Evolution
T.-L. Ashman
A. Bledsoe
S. Kalisz
J. Lawrence
Z.-X. Luo
R. Relyea
S. Shostak
S. Tonsor
B. Traw

Genetics
K. Arndt
T.-L. Ashman
G. Campbell
D. Chapman
G. Hatfull
J. Hildebrand
L. Jacobson
S. Kalisz
J. Martens
W. Saunders
B. Stronach
S. Tonsor
R. Wood

Microbiology
J. Boyle
G. Hatfull
R. Hendrix
J. Lawrence
J. Pipas
M. Popa
R.L. Duda
S. Godfrey
V. Oke

Molecular Biology
K. Arndt
J. Franzen
P. Grabowski
G. Hatfull
R. Hendrix
L. Jen-Jacobson
J. Martens
C. Peebles
J. Pipas
J. Rosenberg
A. Schwacha
C. Walsh

Plant Biology
T.-L. Ashman
W. Carson
S. Kalisz
V. Oke
C. Partanen
S. Tonsor
B. Traw

Science Education
A. Bledsoe
K. Curto
L. Daniels
S. Godfrey
N. Kaufmann
C. LaFave
J. Newman
E. Polinko
M. Popa
L. Roberts
T. Seiflein
R. Sherwin
A. Slinskey Legg

Structural Biology
M. Grabe
J. Hempel
R. Hendrix
L. Jen-Jacobson
J. Rosenberg
A. VanDemark

Former Faculty

Professional Interests - Publications - Contact Information - Lab Personnel

Professional Interests of Beth Roman

Blood vessels in development and disease
The vertebrate vascular system supports development of all other organs by delivering an adequate supply of oxygenated blood. During embryonic stages, globally abnormal blood vessel development will result in embryonic death. But even localized vessel abnormalities that arise during development can be of serious consequence, either embryonically or later in life. For example, vessel malformations frequently arise during the remodeling of the embryonic aortic arches to form the arch of the aorta and associated great arteries, with outcomes ranging from partial airway and esophageal obstruction to congestive heart failure. And localized arteriovenous malformations, in which arteries connect directly to veins without intervening capillaries, can lead to hemorrhagic or ischemic stroke. Identifying the molecular pathways that control embryonic blood vessel growth will enable us to understand the etiology of these and other developmental vascular disorders, and should also contribute to the development of therapies to inhibit or enhance blood vessel growth in the treatment of cancer and cardiovascular obstructive diseases, respectively, as the pathways that control developmental and disease-associated vessel growth are largely shared.

Figure 1. Circulation is easily visualized in the live zebrafish embryo, 2 days post-fertilization. Movie. Click here to see blood cells in motion through the dorsal aorta, caudal vein, and intersegmental vessels (ISV). Initial magnification is 100x; 200x view is focused on the caudal vein. Lateral view, anterior to the left. This movie is 43 MB in size.

Zebrafish as a model for blood vessel development
Zebrafish are a great model system for answering questions about vertebrate development. Female zebrafish lay, on average, 200 eggs per mating, and these eggs are externally fertilized and thus accessible. The resulting embryos develop very quickly, going from a single cell to a free-swimming larva just three days. And zebrafish embryos are transparent, allowing us to effectively watch development happen in real time, in live embryos. Moreover, zebrafish are amenable to forward genetic screens, which involve introduction of random mutations into the germline of adult fish, screening of descendants for phenotypic defects, and identification of the mutated genes by positional cloning. Thus, zebrafish allow us to take an unbiased approach to uncovering novel players in critical developmental pathways. Simply by observing blood flow in the transparent, live embryo (Fig. 1), we have identified zebrafish mutants with normal heartbeats but abnormal circulation patterns, suggesting problems with blood vessel development. Two of these mutants, violet beauregarde and kurzschluss, are being studied in depth in our laboratory.

1. Zebrafish as a model for Hereditary Hemorrhagic Telangiectasia (HHT)
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that affects up to 1 in 5000 people worldwide. This disease is most often caused by mutations in either Endoglin (HHT1) or Alk1 (HHT2), two endothelial-specific TGFb family receptors that help to transmit signal from an extracellular ligand to the nucleus, ultimately resulting in changes in gene transcription. If these receptors do not function properly, vascular lesions known as telangiectases and arteriovenous malformations (AVMs) can result. These lesions arise when arteries connect directly to veins instead of being bridged by a network of capillaries. Telangiectases occur in small vessels, particularly in mucous membranes and in the gastrointestinal tract. AVMs occur in large vessels, especially in the brain, lung, and liver. While the former can lead to frequent nose bleeds and, rarely, serious hemorrhages, the latter can lead to stroke if severe shunting or rupture occurs.

Figure 2. Particular cranial arteries (arrows) are enlarged in vbg mutants. In the absence of Alk1 function, these vessels contain too many endothelial cells and make aberrant connections to neighboring veins (asterisk). A, wild type; B, vbg mutant. Note that these embryos harbor a stable transgene that directs expression, via the vegfr2 promoter, of green fluorescent protein (GFP) to the endothelium, allowing visualization of all blood vessels. Dorsal views, anterior to the left. Images were captured using a Fluoview 500 laser scanning confocal microscope.

While it is well established that mutations in Alk1 lead to HHT2, the role of this receptor within the endothelial cell is unknown, and the mechanism by which telangiectases and AVMs form in its absence remains a mystery. Our laboratory is using the zebrafish to try to shed light on these problems. We identified a recessive lethal zebrafish alk1 mutant (violet beauregarde, or vbg) from a large-scale mutagenesis screen, and showed that loss of Alk1 function in zebrafish leads to enlarged cranial blood vessels that exhibit aberrant connections between arteries and veins (Figure 2; Roman et al., 2002). Importantly, we showed that these enlarged vessels contain twice the number of endothelial cells as their wild type counterparts, suggesting that the role of Alk1 is to inhibit the activation phase of angiogenesis (which involves endothelial cell migration and proliferation) and/or to promote the resolution phase of angiogenesis (which involves cessation of migration and proliferation and stabilization of nascent vessels). Studies are currently focused on defining the source of these extra endothelial cells (excess proliferation, migration, sprouting?) and identifying downstream targets of Alk1 activation. Taken together, this information should allow us to better understand the role of Alk1 within the endothelium and to define at least one mechanism by which congenital AVMs form.

2. Zebrafish as a model for congenital aortic arch abnormalities
Congenital cardiovascular anomalies are the most common type of birth defect reported, and a large number of these defects involve lesions in the arch of he aorta and associated vessels. While most lesions are thought to be the result of aberrant remodeling of the embryonic aortic arches (which initially evolved to feed the gills) into the arch of the aorta and associated vessels, the true origin of most lesions is completely unknown. Using the zebrafish, we are making strides in defining the developmental origin of the aortic arches, and identifying tissue interactions within the broader context of the surrounding pharyngeal arches that help to support proper aortic arch growth and development. Furthermore, we have identified a zebrafish mutant, kurzschluss (kus), that exhibits aberrant connections between the posterior aortic arches (gill arches) and a major cranial vein, creating an AVM that shunts nearly all cardiac output directly back to the heart (Figure 3, below). Positional cloning of kus has uncovered a novel player in vascular development that seems to function not within the endothelium but within surrounding tissues, emphasizing the critical importance of tissue interactions in patterning the pharyngeal region. Furthermore, phenotypic studies suggest that the AVM that forms in kus arises in a very different manner from the AVM in vbg. Continuing studies are focused on defining extravascular lesions in kus mutants and attributing a cellular function to the kus gene.

Figure 3: An arteriovenous malformation (asterisk) connecting aortic arch 5 (AA5) to the primary head sinus (PHS), a major cranial vein, is the hallmark of the kus phenotype. Note how aortic arch 5 passes beneath the PHS in the wild type embryo (A) but merges with it in kus (B). These embryos are expressing two fluorescent transgenes, vegfr2-driven GFP and gata1-driven dsRed, so blood vessels look green and red blood cells look red. Lateral views, anterior to the left. Images were captured using a Fluoview 500 laser scanning confocal microscope.

Publication Archive
13 Citations
11 Abstracts
9 PDFs

Recent Publications of Beth Roman

Anderson, M.J., V.N. Pham, A.M. Vogel, B.M. Weinstein, and B.L. Roman (2008) Loss of unc45a precipitates arteriovenous shunting in the aortic arches. Dev. Biol. 318:258-267

Park, S.O., Y.J. Lee, T. Seki, K.H. Hong, N. Fliess, Z. Jiang, A. Park, X. Wu, V. Kaartinen, B.L. Roman, and S.P. Oh (2008) ALK5- and TGFBR2-independent role of ALK1 in the pathogenesis of hereditary hemorrhagic telangiectasia type 2 (HHT2). Blood 111:633-642

Roman, B.L., V.N. Pham, N.D. Lawson, M. Kulik, S. Childs, A.C. Lekven, D.M. Garrity, R.T. Moon, M.C. Fishman, R.J. Lechleider, and B.M. Weinstein (2002) Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development 129:3009-3019 (PDF Reprint: 538 kb)

Pham, V.N., B.L. Roman, and B.M. Weinstein (2001) Isolation and expression analysis of three zebrafish angiopoietin genes. Dev. Dynam. 221:470-474 (PDF Reprint: 349 kb)

Roman, B.L., and B.M. Weinstein (2000) Building the vertebrate vasculature: research is going swimmingly. Bioessays 22:882-893 (PDF Reprint: 366 kb)

Motoike, T., S. Loughna, E. Perens, B.L. Roman, W. Liao, T.C. Chau, C.D. Richardson, T. Kawate, J. Kuno, B.M. Weinstein, D.Y. Stainier, and T.N. Sato (2000) Universal GFP reporter for the study of vascular development. Genesis 28:75-81 (PDF Reprint: 588 kb)

Theobald, H.M., B.L. Roman, T.M. Lin, S. Ohtani, S.W. Chen, and R.E. Peterson (2000) 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibits luminal cell differentiation and androgen responsiveness of the ventral prostate without inhibiting prostatic 5alpha-dihydrotestosterone formation or testicular androgen production in rat offspring. Toxicol. Sci. 58:324-338 (PDF Reprint: 382 kb)

How to Contact Beth Roman

 
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