Biography
MOLECULAR PROGRAMMING OF THE VASCULATURE IN DEVELOPMENT AND DISEASE
Proper formation and function of the vasculature are crucial for health and survival, as the vasculature supplies all cells in the body. A dysfunctional vasculature causes myriad diseases, including stroke, arterial occlusive diseases, and vascular anomalies. Our long-term goal is to identify novel drug targets and inform rational therapeutic designs to treat vascular diseases. Our strategy is to understand genes crucial for angiogenesis (new vessel formation) in the normal and diseased states, concentrating on the Notch, ephrin-B2, and TGF-beta pathways. We employ cutting-edge mouse genetics to delete or express genes in a cell lineage-specific and temporally controllable fashion in vascular cells. We combine these molecular approaches with mouse models of diseases as well as live 5D two-photon imaging (3D + blood flow over time) to uncover both the molecular mechanisms and hemodynamic signals in development and disease progression. These preclinical animal studies are coupled with patient sample validations. Our lab members come from diverse fields, including biology, bioengineering, and medicine, creating a collaborative and exciting environment. We strive to advance multiple projects across disciplines.
PROJECTS
Molecular programming of blood vessels: Building on our study of the developing dorsal aorta and cardinal vein, the first major artery-vein (AV) pair to form in the body, our lab aims to identify molecular regulators that program arteries and veins in vital organs during development and aging. We examine the interplay between genetic AV programming and flow-induced patterning. Understanding AV programming in normal angiogenesis provides important insights into how the genetic pathways can be hijacked in various disease states.
Stroke: We study two types of stroke, ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when arteries supplying the brain are blocked. Using a surgical model of ischemic stroke, we aim to identify technologies enabling better recover following arterial blockade. Hemorrhagic stroke, on the other hand, occurs when diseased blood vessels rupture. Brain arteriovenous malformations (AVMs), which are direct connections from arteries to veins, are one of the major causes of hemorrhagic stroke. We investigate AV programming in both AVM progression and regression.
Arteriovenous malformations: AVMs can occur anywhere in the body and comprise a category of hard to treat vascular anomalies. Most AVMs are sporadic, thus limiting the understanding of their etiology. In contrast, hereditary AVMs, such as those found in hereditary hemorrhagic telangiectasia (HHT) patients, offer an excellent opportunity to study how AVMs form. HHTs are caused by mutations in genes of the TGF-beta superfamily. We are interested in the molecular mechanisms underlying HHT-mediated AVMs formation.
Arterial occlusive diseases: Arterial occlusive diseases occur when the arteries in the body are blocked, causing insufficient blood flow to the tissues. Blockage of arteries in the brain causes stroke, in the heart causes myocardial infarction, and in the extremities causes peripheral arterial disease. Arteriogenesis, a process by which small dormant arteries around the blockage enlarge to form collateral circulation, holds promise to restore blood flow and rescue affected tissues. We investigate pro-arteriogenic molecular regulators to uncover potential therapeutic strategies to enhance the body’s natural defense against arterial occlusive disease.
Proper formation and function of the vasculature are crucial for health and survival, as the vasculature supplies all cells in the body. A dysfunctional vasculature causes myriad diseases, including stroke, arterial occlusive diseases, and vascular anomalies. Our long-term goal is to identify novel drug targets and inform rational therapeutic designs to treat vascular diseases. Our strategy is to understand genes crucial for angiogenesis (new vessel formation) in the normal and diseased states, concentrating on the Notch, ephrin-B2, and TGF-beta pathways. We employ cutting-edge mouse genetics to delete or express genes in a cell lineage-specific and temporally controllable fashion in vascular cells. We combine these molecular approaches with mouse models of diseases as well as live 5D two-photon imaging (3D + blood flow over time) to uncover both the molecular mechanisms and hemodynamic signals in development and disease progression. These preclinical animal studies are coupled with patient sample validations. Our lab members come from diverse fields, including biology, bioengineering, and medicine, creating a collaborative and exciting environment. We strive to advance multiple projects across disciplines.
PROJECTS
Molecular programming of blood vessels: Building on our study of the developing dorsal aorta and cardinal vein, the first major artery-vein (AV) pair to form in the body, our lab aims to identify molecular regulators that program arteries and veins in vital organs during development and aging. We examine the interplay between genetic AV programming and flow-induced patterning. Understanding AV programming in normal angiogenesis provides important insights into how the genetic pathways can be hijacked in various disease states.
Stroke: We study two types of stroke, ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when arteries supplying the brain are blocked. Using a surgical model of ischemic stroke, we aim to identify technologies enabling better recover following arterial blockade. Hemorrhagic stroke, on the other hand, occurs when diseased blood vessels rupture. Brain arteriovenous malformations (AVMs), which are direct connections from arteries to veins, are one of the major causes of hemorrhagic stroke. We investigate AV programming in both AVM progression and regression.
Arteriovenous malformations: AVMs can occur anywhere in the body and comprise a category of hard to treat vascular anomalies. Most AVMs are sporadic, thus limiting the understanding of their etiology. In contrast, hereditary AVMs, such as those found in hereditary hemorrhagic telangiectasia (HHT) patients, offer an excellent opportunity to study how AVMs form. HHTs are caused by mutations in genes of the TGF-beta superfamily. We are interested in the molecular mechanisms underlying HHT-mediated AVMs formation.
Arterial occlusive diseases: Arterial occlusive diseases occur when the arteries in the body are blocked, causing insufficient blood flow to the tissues. Blockage of arteries in the brain causes stroke, in the heart causes myocardial infarction, and in the extremities causes peripheral arterial disease. Arteriogenesis, a process by which small dormant arteries around the blockage enlarge to form collateral circulation, holds promise to restore blood flow and rescue affected tissues. We investigate pro-arteriogenic molecular regulators to uncover potential therapeutic strategies to enhance the body’s natural defense against arterial occlusive disease.
Videos
Education
Institution | Degree | Dept or School | End Date |
---|---|---|---|
University of California | Diversity, Equity, and Inclusion Champion Training | 2019 | |
University of California, San Francisco | Coro-UCSF Collaborative | Faculty Leadership Training | 2008 |
University of California, San Francisco | Postdoctoral Fellowship | Cancer Biology | 1999 |
University of North Carolina, Chapel Hill | Ph.D. | Biology (Angiogenesis) | 1993 |
Graduate School of Chinese Science and Technology University, Institute of Genetics, Academia Sinica | M.S. Candidate | Mammalian Genetics | 1988 |
Sichuan University | B.S. | Biology | 1984 |
In the News
Grants and Funding
- Molecular Pathogenesis of Hereditary Hemorrhagic Telangiectasia | NINDS | 2020-02-01 - 2025-01-31 | Role: Principal Investigator
- Molecular Pathogenesis of Hereditary Hemorrhagic Telangiectasia | NIH | 2020-02-01 - 2025-01-31 | Role: Principal Investigator
- Identifying Molecular Regulators of Hereditary Hemorrhagic Telangiectasia In a Novel Mouse Model | American Heart Association | 2019-07-01 - 2022-06-30 | Role: Principal Investigator
- Molecular Pathogenesis and Therapy for Critical Lim Ischemia | Tobacco Related Disease Research Program | 2018-07-01 - 2021-06-30 | Role: Principal Investigator
- RBPJ and EphrinB2 as Molecular Targets to Treat Brain Arteriovenous Malformation in Notch4-Induced Mouse Models | Department of the Army | 2016-09-30 - 2020-09-30 | Role: Principal Investigator
- Molecular Pathogenesis of Brain Arteriovenous Malformation | NIH | 2010-08-01 - 2020-03-31 | Role: Principal Investigator
- Notch Signaling in Arterial-Venous Specification | NIH | 2003-12-01 - 2017-02-28 | Role: Principal Investigator
Research Interests
- Angiogenesis Inhibitors
- Neovascularization
- Physiologic, Ischemia
- Developmental Biology
- Gene Expression Regulation
- Embryonic Development
- Developmental Growth
- Arteriovenous Malformations
- Carcinoma, Hepatocellular
- Arteriogenesis
- Notch Pathway
- EphrinB2
- Vascular Development
- Collateral Vessel Formation
- Vascular Physiology
- Stem Cells
Publications
MOST RECENT PUBLICATIONS FROM A TOTAL OF 43
- Site-specific protein conjugates incorporating Para-Azido-L-Phenylalanine for cellular and in vivo imaging.| | View in PubMed
- Meeting Proceedings from ICBS 2022 - Uncovering Solutions for Diseases.| | View in PubMed
- Nitric oxide synthase and reduced arterial tone contribute to arteriovenous malformation.| | View in PubMed
- Monitoring of cell-cell communication and contact history in mammals.| | View in PubMed
- Endothelial Rbpj deletion normalizes Notch4-induced brain arteriovenous malformation in mice.| | View in PubMed
- Mechanical Stretch Increases Expression of CXCL1 in Liver Sinusoidal Endothelial Cells to Recruit Neutrophils, Generate Sinusoidal Microthombi, and Promote Portal Hypertension.| | View in PubMed
- Abnormal arterial-venous fusions and fate specification in mouse embryos lacking blood flow.| | View in PubMed
- Endothelial notch signaling is essential to prevent hepatic vascular malformations in mice.| | View in PubMed
- Mouse Models of Cerebral Arteriovenous Malformation.| | View in PubMed
- Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels.| | View in PubMed
- Endothelial ephrin-B2 is essential for arterial vasodilation in mice.| | View in PubMed
- Deletion of Rbpj from postnatal endothelium leads to abnormal arteriovenous shunting in mice.| | View in PubMed
- Molecular identification of venous progenitors in the dorsal aorta reveals an aortic origin for the cardinal vein in mammals.| | View in PubMed
- Notch4 is required for tumor onset and perfusion.| | View in PubMed
- Line-scanning particle image velocimetry: an optical approach for quantifying a wide range of blood flow speeds in live animals.| | View in PubMed
- Notch4 normalization reduces blood vessel size in arteriovenous malformations.| | View in PubMed
- Inefficient skeletal muscle repair in inhibitor of differentiation knockout mice suggests a crucial role for BMP signaling during adult muscle regeneration.| | View in PubMed
- Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice.| | View in PubMed
- Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation.| | View in PubMed
- Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease.| | View in PubMed
- Cellular and molecular mechanism regulating blood flow recovery in acute versus gradual femoral artery occlusion are distinct in the mouse.| | View in PubMed
- Artery and vein size is balanced by Notch and ephrin B2/EphB4 during angiogenesis.| | View in PubMed
- Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice.| | View in PubMed
- Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function.| | View in PubMed
- c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo.| | View in PubMed
- Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice.| | View in PubMed
- Distinct pathways of genomic progression to benign and malignant tumors of the liver.| | View in PubMed
- Endothelial FAK is essential for vascular network stability, cell survival, and lamellipodial formation.| | View in PubMed
- Optimization of adenovirus-mediated endothelial nitric oxide synthase delivery in rat hindlimb ischemia.| | View in PubMed
- Vascular development of the brain requires beta8 integrin expression in the neuroepithelium.| | View in PubMed
- Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice.| | View in PubMed
- VEGF is crucial for the hepatic vascular development required for lipoprotein uptake.| | View in PubMed
- The effect of gradual or acute arterial occlusion on skeletal muscle blood flow, arteriogenesis, and inflammation in rat hindlimb ischemia.| | View in PubMed
- Genomic progression in mouse models for liver tumors.| | View in PubMed
- CCR2-/- knockout mice revascularize normally in response to severe hindlimb ischemia.| | View in PubMed
- Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb.| | View in PubMed
- Activation of the Met receptor by cell attachment induces and sustains hepatocellular carcinomas in transgenic mice.| | View in PubMed
- European surveillance of infections and risk factors in cancer patients.| | View in PubMed
- Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor.| | View in PubMed
- Developmental analysis of bone tumors in polyomavirus transgenic mice.| | View in PubMed
- Embryonic stem cell-derived cystic embryoid bodies form vascular channels: an in vitro model of blood vessel development.| | View in PubMed
- Isolation and characterization of an established endothelial cell line from transgenic mouse hemangiomas.| | View in PubMed
- The polyomavirus early region gene in transgenic mice causes vascular and bone tumors.| | View in PubMed