Research Summary:
Research in my lab is focused on angiogenesis, or new blood vessel formation, which is a critical process in development and disease. My lab aims to advance the fundamental understanding of the cellular, molecular, and hemodynamic mechanisms underlying arterial-venous programming in normal and pathological angiogenesis. We use cutting-edge mouse genetics to delete or express genes in a cell lineage-specific and temporally controllable fashion in endothelial cells. This advance is crucial for the study of candidate genes in vascular function, especially when combined with sophisticated 5D two-photon imaging (3D + blood flow over time). These innovative approaches provide us with exceptional access to gene function in both healthy and pathological conditions in living animals. This basic approach is complemented by preclinical studies with patient samples in addition to our mouse models of disease. In particular, we investigate the molecular regulators governing arterial-venous programming – particularly the Notch, ephrin-B2, and TGF-beta signaling pathways – in both normal and pathological conditions.
Ongoing projects:
Vascular Development. Our lab aims to identify molecular regulators of arterial and venous cell fate determination and morphogenesis in embryonic development. We primarily focus on the origin and morphogenesis of the dorsal aorta and cardinal vein, the first major artery-vein pair to form in the body.
Arteriovenous Malformation (AVM). AVMs are severe vascular anomalies that shunt blood directly from arteries to veins, displace intervening capillaries, and bypass tissues. My lab studies the pathogenesis and regression of AVMs. We have a long history of investigation using animal models into Notch-mediated AVM pathogenesis as well as into potential treatments for the disease.
Arterial occlusive diseases and arteriogenesis. The body responds to arterial occlusions by inducing arteriogenesis, or radial enlargement of arteries, to restore circulation to blood-deprived tissue. We are investigating pro-arteriogenic molecular regulators to uncover potential therapeutic targets, which may be used to enhance the body’s natural defense against arterial occlusive disease.
Cancer. Solid tumors induce arteriogenesis to support their growth. We investigate the molecular stimulators of arteriogenesis in tumor progression and regression, particularly in hepatocellular carcinoma (HCC), which is characterized by large and highly arterialized tumor masses in the liver. We study genes regulating tumor arterial growth and modify these genes to target tumor arterial supply and to inhibit HCC growth.
Ultimately, through these distinct but interconnected fields of study, we hope to identify novel drug targets and inform rational design of new therapeutics to treat human disease.
Publications
Metabolic Probing of Sialylated Glycoconjugates with Fluorine-Selenol Displacement Reaction (FSeDR).
Flexible Fluorine-Thiol Displacement Stapled Peptides with Enhanced Membrane Penetration for the Estrogen Receptor/Coactivator Interaction.
Site-specific protein conjugates incorporating Para-Azido-L-Phenylalanine for cellular and in vivo imaging.
Meeting Proceedings from ICBS 2022 - Uncovering Solutions for Diseases.
Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation.
Monitoring of cell-cell communication and contact history in mammals.
Endothelial Rbpj deletion normalizes Notch4-induced brain arteriovenous malformation in mice.
Abnormal arterial-venous fusions and fate specification in mouse embryos lacking blood flow.
Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice.
Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels.
Endothelial ephrin-B2 is essential for arterial vasodilation in mice.
Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice.
Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals.
Notch4 is required for tumor onset and perfusion.
Notch4 normalization reduces blood vessel size in arteriovenous malformations.
Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration.
Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice.
Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.
Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease.
Cellular and molecular mechanism regulating blood flow recovery in acute versus gradual femoral artery occlusion are distinct in the mouse.
Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis.
Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice.
Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function.
c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo.
Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice.
Distinct pathways of genomic progression to benign and malignant tumors of the liver.
Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation.
Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia.
Vascular development of the brain requires beta8 integrin expression in the neuroepithelium.
Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice.
VEGF is crucial for the hepatic vascular development required for lipoprotein uptake.
The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia.
Genomic progression in mouse models for liver tumors.
CCR2-/- knockout mice revascularize normally in response to severe hindlimb ischemia.
Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb.
Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice.
European surveillance of infections and risk factors in cancer patients.
Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor.
Developmental analysis of bone tumors in polyomavirus transgenic mice.
Embryonic stem cell-derived cystic embryoid bodies form vascular channels: an in vitro model of blood vessel development.
Isolation and characterization of an established endothelial cell line from transgenic mouse hemangiomas.
513 Parnassus Avenue, HSW, Rm 1618
UCSF Box 0222
San Francisco, CA 94143
United States