Possible Rotation Projects:
- Use mosaic zebrafish HHT models to gain insight into cellular and molecular mechanisms of AVM development
- Apply genome editing, transgenesis, and computational analysis to define cis elements and trans-acting factors that specify spatiotemporal patterns of ACVRL1 expression in human and zebrafish endothelial cells
- Test de novo-designed ligands for ALK1 agonist activity in cell culture models
Training Technologies Used:
- Zebrafish development and genetics, Confocal microscopy, Molecular biology, Genome editing, Drug development
- Ph.D. in Environmental Toxicology from University of Wisconsin Madison, 1997
- B.S. in Biochemistry from Penn State, 1989
Anzell AR, White CM, Diergaarde B, Carlson JC, and Roman BL. Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1. Circ Genom Precis Med, 2025. 18(5): p. e005061. https://www.ncbi.nlm.nih.gov/pubmed/40964703.
Schwartze TA, Morosky SA, Rosato TL, Henrickson A, Lin G, Hinck CS, Taylor AB, Olsen SK, Calero G, Demeler B, Roman BL, and Hinck AP. Molecular Basis of Interchain Disulfide Bond Formation in BMP-9 and BMP-10. J Mol Biol, 2025. 437(4): p. 168935. PMC12148503. https://www.ncbi.nlm.nih.gov/pubmed/39793884.
Spanou CES, Yang C, Godwin ARF, Morosky S, Anbalagan A, Lutke S, Morgelin M, Marcous F, Aziz U, Wohl AP, Jabeen I, Koch M, Jowitt TA, Roman BL, Tarakanova A, Baldock C, and Sengle G. Prodomain processing controls BMP-10 bioactivity and targeting to fibrillin-1 in latent conformation. FASEB J, 2025. 39(3): p. e70373. PMC11806408. https://www.ncbi.nlm.nih.gov/pubmed/39921464.
Anzell AR, Kunz AB, Donovan JP, Tran TG, Lu X, Young S, and Roman BL. Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity. Angiogenesis, 2024. 27(3): p. 501-522. PMC12551676. https://www.ncbi.nlm.nih.gov/pubmed/38727966.
Cheng YW, Anzell AR, Morosky SA, Schwartze TA, Hinck CS, Hinck AP, Roman BL, and Davidson LA. Shear Stress and Sub-Femtomolar Levels of Ligand Synergize to Activate ALK1 Signaling in Endothelial Cells. Cells, 2024. 13(3). PMC10854672. https://www.ncbi.nlm.nih.gov/pubmed/38334677.
Arthur HM and Roman BL. An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms. Front Med (Lausanne), 2022. 9: p. 973964. PMC9556665. https://www.ncbi.nlm.nih.gov/pubmed/36250069.
Capasso TL, Trucco SM, Hindes M, Schwartze T, Bloch JL, Kreutzer J, Cook SC, Hinck CS, Treggiari D, Feingold B, Hinck AP, and Roman BL. In Search of "Hepatic Factor": Lack of Evidence for ALK1 Ligands BMP9 and BMP10. Am J Respir Crit Care Med, 2021. 203(2): p. 249-251. PMC7874408. https://www.ncbi.nlm.nih.gov/pubmed/32871084.
Capasso TL, Li B, Volek HJ, Khalid W, Rochon ER, Anbalagan A, Herdman C, Yost HJ, Villanueva FS, Kim K, and Roman BL. BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance. Angiogenesis, 2020. 23(2): p. 203-220. PMC7165044. https://www.ncbi.nlm.nih.gov/pubmed/31828546.
Rochon ER, Krowka MJ, Bartolome S, Heresi GA, Bull T, Roberts K, Hemnes A, Forde KA, Krok KL, Patel M, Lin G, McNeil M, Al-Naamani N, Roman BL, Yu PB, Fallon MB, Gladwin MT, and Kawut SM. BMP9/10 in Pulmonary Vascular Complications of Liver Disease. Am J Respir Crit Care Med, 2020. 201(12): p. 1575-1578. PMC7301744. https://www.ncbi.nlm.nih.gov/pubmed/32083953.
Sonmez UM, Cheng YW, Watkins SC, Roman BL, and Davidson LA. Endothelial cell polarization and orientation to flow in a novel microfluidic multimodal shear stress generator. Lab Chip, 2020. 20(23): p. 4373-4390. PMC7686155. https://www.ncbi.nlm.nih.gov/pubmed/33099594.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular and bleeding disorder that affects more than 1 in 5000 people worldwide. It is caused by disruption of bone morphogenetic protein (BMP)/endoglin/ALK1 signaling in endothelial cells and results in development of arteriovenous malformations (AVMs), which are direct connections between arteries and veins. Rupture of these malformations in the nose or gastrointestinal tract can lead to severe anemia, whereas rupture in the brain can lead to hemorrhagic stroke. Additionally, shunting of blood through these malformations—which diverts blood around the capillaries—can lead to shortness of breath, embolic stroke, or heart failure. Despite pathway knowledge, there are no targeted therapies for HHT.
We use zebrafish to understand HHT disease pathogenesis. Taking advantage of the fact that zebrafish embryos are externally fertilized, optically transparent, and fast-developing, we apply time-lapse confocal imaging to noninvasively watch blood vessels – and AVMs – form in real time in robust genetic models of HHT. Using these models, we discovered that the physical forces of blood flow interact with ALK1 signaling to control endothelial cell ALK1 expression, endothelial cell migration, and AVM site selection and growth. We also discovered a key role for the endocrine ALK1 ligand, BMP10, in AVM prevention. Currently, we are studying endothelial cell behaviors in mosaic loss-of-function models, which more accurately reflect the human disease. We are also using the zebrafish to examine the genomic elements that drive alk1 expression in a subpopulation of arterial endothelial cells and to define key transcriptional targets of Bmp10/Endoglin/Alk1 signaling that are required to prevent development of AVMs.
In addition to zebrafish, we use cultured human cells to study how ALK1 ligands, BMP9 and BMP10, are processed and secreted and to understand how they signal on endothelial cells. In collaboration with protein designers and structural biologists, we are developing “biobetters” – de novo-designed proteins that exhibit enhanced efficacy, reduced toxicity, and longer half-life compared to endogenous ligands—with the goal of developing a targeted therapeutic for HHT. Finally, in collaboration with the UPMC HHT Center of Excellence, we are building a blood and tissue repository to enable clinical research.
