CVRI Scientists

Developmental biology and congenital anomalies

Brian L Black, Ph.D.
Professor

Research Interests:
Cardiac and skeletal muscle development, differentiation, and function

Summary:
Congenital heart anomalies are the most common form of birth defect in the United States, affecting nearly one percent of all babies, yet the molecular and developmental basis for these defects is largely unknown. Tissues and organs form during mammalian embryonic development because of the integration of numerous signaling and transcriptional pathways. Our major goal is to define these pathways in order to understand the molecular causes of congenital anomalies and potential mechanisms for organ regeneration and repair. Using the mouse as a model system, the current work in the lab is focused on defining the pathways regulating the development of cardiac and skeletal muscle, the vascular endothelium, and neural crest. Specific projects focus on the regulation and function of genes that are known to be critical for cardiac development. These include Mef2c, Islet1, Gata4, Bmp4, and Fgf8. Each of these genes is involved in cardiac development, and we are defining their regulation and function specifically during the formation of the cardiac outflow tract, one of the most commonly and severely affected regions of the heart observed in babies. The long-term scientific goal of these studies is to define the how tissues and cells are integrated during organogenesis and how cells receive and interpret positional information. We are using a combination of conditional gene knockouts, transgenic reporter assays, and fate mapping techniques in mice to define the embryological origins of the outflow tract and the reciprocal signaling between tissues that is required for proper heart development. The ultimate goal of these studies is to development diagnostic and therapeutic interventions for birth defects of the heart and other organ systems.

Benoit G Bruneau, B.Sc., Ph.D.
Associate Professor

Research Interests:
Heart development, congenital heart disease, chromatin, embryogenesis, transcription

Summary:
Our laboratory studies the genes that direct a cell to become a heart cell, focusing on the machinery within each cell that turns genes on or off. Many of these factors are implicated in human congenital heart disease, and our studies also focus on understanding the basis of these diseases.

Pao-Tien Chuang, M.D. , Ph.D.
Professor

Research Interests:
Cell-cell signaling during mammalian development and in postnatal physiology

Summary:
We use mouse as a model system to understand how embryos develop. This knowledge is critical for understanding the basis of human congenital defects. Moreover, many adult diseases have their origin in development. Thus, our studies have important implications for developing stem cell therapy and identifying the cause of cancers.

Ronald I Clyman, M.D.
Prof In Rsdn Ped & CVRI

Research Interests:
Cardiology, Cell Biology, Developmental Biology, Neonatology, Neonatal Cardiology

Summary:
The ductus arteriosus is a vital fetal blood vessel that diverts blood away from the fetus's lungs and towards the placenta during life inside the uterus. After birth it is essential that the ductus arteriosus constricts and obliterates itself so that the normal postnatal pattern of blood flow can be established. Essentially all full term infants will have closed their ductus by the third day after birth. Preterm infants of less than 30 weeks gestation have a high chance of having a persistently open or patent ductus arteriosus (PDA). If the ductus arteriosus remains open it contributes to the development of several neonatal morbidities: prolonged ventilator dependency, pulmonary hemorrhage, pulmonary edema, chronic lung disease and necrotizing enterocolitis. Our laboratory has been studying the factors that regulate normal closure of the ductus arteriosus in full term infants and abnormal persistent ductal patency in preterm infants. Approaches used to study this problem are: controlled clinical trials, integrated whole animal physiology, in vitro organ culture, and cell biology

Bruce R Conklin, M.D.
Professor In Residence

Research Interests:
Engineering Hormone Signaling Pathways In Vivo

Summary:
Hormone receptors direct the development and function of complex tissues, including those found in the cardiovascular system. The focus of our research is on the largest known family of receptors for hormones and drugs, the G protein–coupled receptors. We combine genetic engineering, stem cells and new computer programs to find new treatments of cardiovascular disease.

Shaun R Coughlin, M.D., Ph.D.
Professor

Research Interests:
Signaling mechanisms in cardiovascular biology and disease, thrombin signaling

Summary:
My laboratory seeks to define signaling mechanisms that govern cardiovascular biology and disease, with a focus on G protein-coupled receptors (GPCRs). We discovered and characterized protease-activated receptors (PARs), a family of GPCRs that permit thrombin and related proteases to regulate the behavior of platelets and other cells. Together with the coagulation cascade, these receptors link tissue injury to cellular responses that regulate blood clotting, inflammation, pain sensation, and perhaps cytoprotection and repair. PARs are necessary for platelet activation by thrombin, and a PAR1 antagonist was recently shown to prevent myocardial infarction and ischemic stroke in patients with known atherothrombotic disease, albeit at the cost of increased bleeding. Current work focuses on better defining the roles and interactions of coagulation factors, PARs and other regulators of hemostasis and thrombosis in mouse and zebrafish models. Additionally, in collaboration with Brian Kobilka, we seek to solve crystal structures of PAR1 off and on states to more fully understand PAR pharmacology and the "tethered ligand" activation mechanism we postulated for these receptors.

PARs also contribute to embryonic development. PAR function in endothelial cells is necessary for normal hemostasis, blood vessel remodeling and/or integrity in midgestation mouse embryos. PAR signaling in surface ectoderm appears to be necessary for neural tube closure; recent findings suggest involvement of local membrane-tethered proteases that regulate epithelial structure and function in part via PARs. Current work utilizes zebrafish and mouse models to identify the molecular and cellular mechanisms underlying these phenomena.

The role of sphingosine-1-phosphate (S1P) signaling via S1P1 and related GPCRs in regulation of vascular permeability is another focus. We found that S1P in the plasma compartment is important for normal vascular permeability/integrity in the adult mouse; current work seeks to determine whether S1P's acting directly on endothelial cell S1P1 mediates this effect and, if so, whether such signaling plays a tonic maintenance function and/or triggers a dynamic response to vascular leak. A second area of focus reflects an unexpected finding made in S1P1 morphant zebrafish embryos generated to better define the roles of S1P1 in the vasculature: S1P1 is necessary for normal sarcomere formation in the developing zebrafish heart. Ongoing work focuses on defining the mechanisms involved and determining whether this system also functions in mammals.

Rik M Derynck, Ph.D.
Professor

Research Interests:
Transmembrane TGF-a and TGF-b receptor signaling in cell proliferation and differentiation.

Summary:
Dr. Derynck studies signaling mechanisms that regulate the generation of bone, muscle and fat cells and how these cells derive from mesenchymal stem cells. This knowledge is used to direct mesenchymal stem cells and pre-adipocytes toward the generation of bone and muscle tissues.

Leland G Dobbs, M.D.
Adjunct Professor

Research Interests:
Pulmonary alveolar epithelial development and response to injury, development of biomarkers for the measurement of lung injury

Summary:
Our laboratory studies the pulmonary alveolar epithelium. More than 99% of the large internal surface area of the lung (in humans ~100-150 m2) is lined by the alveolar epithelium, which is comprised of type I and type II cells, both of which are thought to be essential for mammalian life. Type I cells are very large squamous cells that cover more than 98% of the internal surface area of the lung, providing a narrow anatomic barrier between the air and blood compartments critical for efficient gas exchange. Type II cells are small cuboidal cells characterized by morphologically distinct secretory organelles, lamellar bodies, which contain the intracellular storage pool of pulmonary surfactant. In vivo, type II cells have the capacity to repair injured alveoli, acquiring at least some characteristics of the type I cell phenotype; under these conditions, they appear to transdifferentiate. Current accepted paradigms are that type I cells play a minimal functional role in the lung, but that type II cells perform major alveolar epithelial functions, including acting as progenitor cells during development and after injury. These paradigms do not adequately explain the results of recent experiments in our laboratory. We have developed novel methods for isolating and studying type I cells, which have previously have been resistant to study. Experiments with both in vitro and in vivo models suggest both a major role for the type I cell in ion and fluid transport and revised paradigms for both alveolar epithelial development and response to injury.

Daniel O Hart, PhD
Assistant Professor

Research Interests:
Zebrafish; development; transcription; stem cells

Summary:
The development of a multi-cellular organism from a single cell is a complex process that is regulated at many stages. One important level of regulation is the control of gene expression, that is, how and when genes are switched on or off to produce RNA and proteins. This process, transcriptional regulation, is critical for proper development. Disturbing this important step can have consequences for development and is often a hallmark of disease. It is therefore very important to understand the mechanisms underlying the transcriptional control of gene expression, and this is the broad aim of my lab.

We are particularly interested in understanding how general transcription factors can be used in specific ways to control genes. How they recognize where to bind in the genome, and what other factors (e.g. interacting proteins) may affect how they function to control development and differentiation.

Samuel Hawgood, M.B., B.S., M.D.
Chancellor

Research Interests:
Structure and function of surfactant apoproteins

Summary:
Our research activity is focused on the biology of the pulmonary alveolus with a particular emphasis on the structure and function of the pulmonary surfactant apoproteins. The human lung is made up of some 500 million alveoli each with a diameter of 200 microns and a septal wall thickness of only 5-8 microns. The large surface area provided by this foam-like architecture is ideal for rapid respiratory gas exchange but necessitates some unique biological answers to the threat to structural stability posed by the problem of high surface tension and the constant exposure to environmental pollutants, allergens and microbes. Pulmonary surfactant, a lipoprotein secretion of the alveolar epithelial type II cell, stabilizes alveolar structure at low transpulmonary pressures by reducing the retractile surface forces that would otherwise act to collapse the lung at end expiration. The surfactant apoproteins also act as components of the pulmonary innate defense system protecting the lung from inflammation and infection.

A derangement of alveolar stability, secondary to a developmental deficiency of surfactant, is the major factor in the pathogenesis of the respiratory distress syndrome of the newborn (RDS). My interest in the biology of surfactant grew from clinical experience in neonatology where RDS is a major cause of neonatal death. I moved to UCSF in 1982 as a research fellow with Dr. John Clements, the scientist who discovered surfactant in the late 1950's. He started his own laboratory, focused on the proteins associated with surfactant, in 1984. By 1985 our laboratory had identified three novel surfactant-associated proteins, now known as SP-A, SP-B and SP-C, and had derived their primary structures from full-length cDNA and genomic clones. In 1993, Erica Crouch in St. Louis described a fourth protein, SP-D. The higher-order structure, genetic regulation, metabolism, and function of these proteins have been the focus of our research since that time.

We now know that the surfactant proteins have important roles in the activity of surfactant, particularly the ability to rapidly spread phospholipids at the alveolar surface. The proteins also regulate surfactant turnover and metabolism in the alveolus and play a part in non-antibody mediated response to infection and inflammation in the alveolus. The biology of these proteins is complex and they apparently function as interacting hetero-oligomers to mediate their multiple effects on surfactant biology. At least two of the surfactant proteins, SP-B and SP-C, are present in exogenous surfactants approved for clinical use and fatal human disease has been linked to inherited mutations in both these proteins. This clear link to human disease provides a strong rationale to obtain a detailed understanding of their structure and function.

Julien I Hoffman, M.D., F.R.C.P.
Professor Emeritus

Research Interests:
Pathophysiology of myocardial ischemia

Summary:
My research investigates the way in which the complex muscular architecture of the human heart functions, and what role different components play in heart failure. Current hypotheses of ventricular architecture emphasize the interaction of spiral and circumferential muscle layers, but one major hypothesis that there is a single folded muscular band is much in dispute. We know that the adult pattern is already complete at 14 weeks gestation, but there is no information about how the primitive cardiac tube becomes this complex multilayered structure. My colleagues and I have shown that different components of this muscle band may be affected in diastolic heart failure, and are seeking further information about how components of the band arise and how each component may be affected by disease.

I have ongoing research into the epidemiology of congenital heart disease but no specific problems are being studied at the moment.

Most of my previous research involved the control of the regional coronary circulation, with particular reference to the mechanisms of subendocardial ischemia. Although I am not actively working in this field now, I am collaborating with some bioengineers who are studying these problems.

Guo Huang, Ph.D.
Assistant Prof in Residence

Research Interests:
Comparative study of heart development and regeneration, ischemic heart diseases, stem cell, cardiomyocyte proliferation, regenerative biology

Summary:
The ability to regenerate damaged or lost tissues varies dramatically across organisms and developmental stages. For example, heart regeneration is robust in adult zebrafish and newborn mouse while very limited in adult mouse and human. This presents a particular problem for patients with a heart attack who suffer from a significant loss of heart muscle cells and subsequent life-threatening functional deterioration of the heart.

By taking a comparative approach to study regenerative versus non-regenerative heart repair processes in zebrafish and mouse, we seek to uncover ancestrally conserved injury responses and more importantly, to identify the signals blocking regeneration in the mammalian heart and consequently new treatment strategies for heart diseases.

Natalia Z Jura, PhD
Assistant Professor

Research Interests:
Receptor tyrosine kinases, kinase regulatory mechanisms, membrane proteins, feedback regulation of cell signaling

Summary:
We study basic mechanisms of cellular signaling by Receptor Tyrosine Kinases with a goal to understand how cells receive and process growth signals provided by the neighboring cells and the extracellular milieu. Receptor Tyrosine Kinases are single pass transmembrane receptors that catalyze tyrosine phosphorylation upon activation of their intracellular kinase domains. These receptors are principal regulators of growth and survival signals in cells and therefore frequently become deregulated in human diseases. We are interested in understanding how the kinase activity of these receptors is regulated by ligand binding and how the receptors associate with their regulatory components during the activation process. By combining biochemistry and cell biology we are studying these processes in the reconstituted membrane systems in vitro and in the plasma membrane of the living cells. We also use crystallography to gain an atomic resolution insight into Receptor Tyrosine Kinase regulation that will help us design new approaches for therapeutic intervention

Yuet W Kan, M.D. , D.Sc.
Professor

Research Interests:
The mechanisms of globin production and exploring novel ways of inserting genes into mammalian cells; investigating newer approaches for fetal diagnosis of genetic disorders

Summary:
Sickle cell anemia and thalassemia are the most common genetic diseases and affect people of African, Mediterranean, Middle Ease and Southeast Asian origins. Our laboratory has pioneered the diagnosis of these conditions by DNA tests and is currently investigating the use of patient specific stem cells for their treatment.

Thomas B Kornberg, B.A., Ph.D.
Professor

Research Interests:
Developmental regulation

Summary:
My laboratory investigates the mechanisms that pattern developing organs. We carry out our studies on the fruit fly, as it offers many advantages with its ready accessibility to histological analysis and the ease with which genetic manipulations can be made. We focus on two systems – the fly wing and the fly lung. Both are model systems that offer opportunities to identify and characterize basic genetic and molecular mechanisms that are relevant to human development and disease.

Takashi Mikawa, M.S., Ph.D.
Professor

Research Interests:
Morphogenesis, development, body axis, patterning, cell-to-cell communication, cell architecture, cell fate diversification, cardiovascular system, cardiac conduction system, central nervous system, haemodynamics, growth factor signaling.

Summary:
The establishment of extremely complicated structures and functions of our organ systems depends upon orchestrated differentiation and integration of multiple cell types. Our group focuses to explore a common developmental plan for successful organogenesis, by investigating the mechanisms involved in the differentiation and patterning of the cardiovascular and central nervous systems.

Keith E Mostov, M.D., Ph.D.
Professor

Research Interests:
Polarized epithelial membrane traffic and epithelial morphogenesis.

Summary:
How do individual cells organize to form a multicellular tissue? An individual cell can exhibit many different behaviors - proliferation, migration, adhesion, polarization, differentiation, and death. But to build a tissue, a population of cells must coordinate these individual behaviors across space and time. Little is understood about the mechanisms that orchestrate the actions of single cells during morphogenesis. To analyze these issues, we are studying how epithelial cells form three-dimensional organs. Epithelia are coherent sheets of cells that form a barrier between the interior of the body and the outside world. Internal epithelial organs contain two types of building blocks, cysts and tubules. Our experimental strategy uses culture of epithelial cells in a three-dimensional extracellular matrix. Single cells plated in matrix grow to form hollow cysts lined by a monolayer of cells. We have discovered a pathway containing the small GTPase, rac1, alpha1-beta3 integrin, and laminin, which coordinates cell polarity, so that apical surfaces of the cells are all oriented towards the cyst lumen. Cysts are remodeled into by growth factors, which cause transient dedifferentiation and migration, followed by redifferentiation into polarized epithelial cells lining the tubule.

Spatial asymmetry is fundamental to the structure and function of most eukaryotic cells. A basic aspect of this polarity is that the cell's plasma membrane is divided into discrete domains. The best studied and simplest example of this occurs in epithelial cells, which line exposed body surfaces. Epithelial cells have an apical surface facing the outside world and a basolateral surface contacting adjacent cells and the underlying connective tissue. These surfaces have completely different compositions. Epithelial cells use two pathways to send proteins to the cell surface. Newly made proteins can travel directly from the trans-Golgi network (TGN) to either the apical or basolateral surface. Alternatively, proteins can be sent to the basolateral surface and then endocytosed and transcytosed to the apical surface. We are studying the machinery that is responsible for the specificity and regulation of polarized membrane traffic in epithelial cells. I will discuss several recent results.

1. The SNARE hypothesis provides a unified model for how intracellular vesicular targeting and fusion work. Proteins on transport vesicles, known as v-SNAREs, pair with corresponding t-SNAREs on target membranes, leading to vesicle fusion. The correct pairing of particular v- and t-SNAREs can provide a mechanism for specificity of targeting and fusion. Polarized epithelial cells are an ideal system in which to test the role of SNAREs in specificity, as these cells contain two plasma membrane targets, the apical and basolateral surfaces, as well as multiple classes of vesicles traveling to each surface. We have found that that the t-SNARE syntaxin 3, is involved with transport to the apical surface, while the related t-SNARE, syntaxin 4, is utilized for transport to the basolateral surface.

2. The polymeric immunoglobulin receptor (pIgR) transcytoses IgA from the basolateral to the apical surface. Transcytosis is stimulated by ligand binding. Binding of IgA causes dimerization of the pIgR, which leads to activation of a non-receptor tyrosine kinase, p62Yes. Mice knocked out for this kinase are deficient in IgA transport. Phosphatidylinositol-specific phospholipase C gamma is activated, resulting in production of DAG and IP3. The DAG activates protein kinase Ce, which stimulates transcytosis. The IP3 raises intracellular free calcium, which also stimulates transcytosis. Stimulation of transcytosis also involves the small GTPase, rab3b, which directly interacts with the pIgR.

3. When epithelial cells, such as MDCK cells, are plated in a 3 dimensional collagen matrix, the cells form hollow, polarized cysts with the apical surface facing the lumen of the cyst. Overexpression of a dominant negative form of the small GTPase, rac, retards lumen formation and leads to a partial reversal of polarity, with the apical surface oriented towards the outside of the cyst. Growth of the cysts laminin rescues this phenotype, indicating that interfering with rac function interferes with the ability of the cell to assemble, laminin, which normally provides a spatial cue.

4. When collagen-grown cysts are stimulated with hepatocyte growth factor (HGF), the cysts develop branching tubules, providing a simple model system for studying tubulogenesis. The exocyst is an eight-subunit complex involved in targeting transport vesicles to specific regions of the plasma membrane. We have found that HGF treatment causes the exocyst to relocalize from the region of the tight junction to the growing tubule, indicating that new membrane is being directed to the tubule. Overexpression a subunit of the exocyst, hSec10, causes the cysts to elaborate an increased umber of tubules, indicating a direct connection between membrane traffic and tubulogenesis.

David R Raleigh, M.D., Ph.D.
Assistant Professor In Res

Research Interests:
Hedgehog signaling, developmental biology, brain tumors and molecular therapeutics

Summary:
More children die from brain tumors than any other type of cancer, and the most common type of brain tumor in children is medulloblastoma. Like all cancers, medulloblastoma is caused by uncontrolled cell growth. Approximately one-third of medulloblastoma cancers arise when a particular signal that tells brain cells to grow, called Hedgehog, gets stuck in the 'on' position. We are interested in uncovering exactly how Hedgehog signals tell cancer cells to grow. To do so, we are investigating how the Hedgehog pathway is activated, and how Hedgehog activation regulates the expression of other signals to influence cell growth. Understanding how Hedgehog signals cause cancer may show us how to turn off these signals, and potentially, lead to new therapies for medulloblastoma.

Jeremy F Reiter, M.D., Ph.D.
Associate Professor

Research Interests:
Signaling, primary cilium, stem cell, Hedgehog, Wnt

Summary:
In the process of development, a single egg cell develops into a complex organism. Understanding how that first cell generates such astonishing complexity is one of biology's great tasks. Not only is this task fundamental to our understanding of ourselves, but it is also critical to understanding the causes of birth defects and other diseases. Many of the mechanisms underlying development depend on intercellular communication, the ability of cells to send and receive information. Secreted signaling proteins can communicate many different types of information, from what type of cell a cell should become to whether a cell should live or die. We are studying the mechanisms by which a cellular organelle, the primary cilium, receives and interprets these signals during development. We are also studying how mistakes in these signals contribute to diseases such as cancer.

Jason R. Rock, PhD
Assistant Professor

Research Interests:
Stem cells in lung development, maintenance, and disease

Summary:
We investigate how the many epithelial and stromal cell types of our lungs are generated during development, maintained for a lifetime and regenerated following injury. To do this, we use in vivo and in vitro models to identify and test the progenitor capacity of putative stem cell populations. We posit that aberrant stem cell behaviors explain many features of common lung diseases such as mucous cell hyperplasia and pulmonary fibrosis. For this reason, we study the molecular mechanisms and environmental influences (i.e., niche) that regulate the division and differentiation of stem cells along various lineages. Our ultimate goal is to identify genetic, molecular and cellular therapies for the treatment of lung disease.

David H Rowitch, M.D., Ph.D.
Professor

Research Interests:
Developmental biology, neural tube, CNS cell cycle control and tumorigenesis, cell fate specification, gliogenesis, oligodendrocyte differentiation and myelination, Sonic Hedgehog signaling, transcription factors, Olig bHLH proteins, multiple sclerosis, cerebral palsy, brain cancer.

Summary:
Dr. Rowitch's laboratory investigates common mechanisms in brain development and neurological diseases such as Multiple Sclerosis and brain cancer. Upon moving to UCSF in 2006, Dr. Rowitch has focused on developing a new translational research program focused on Cerebral Palsy, the leading cause of intellectual disability in the United States.

Nelson B Schiller, M.D.
Professor of Cardiology

Research Interests:
Dr. Schiller specializes in the use of echocardiography in the diagnosis and treatment of heart disease. His research interests center around the quantitation of left ventricular function by quantitative two-dimensional echocardiography and Doppler.

Summary:
Measuring the heart has been a preoccupation of civilizations since ancient Egypt. Measuring the heart using noninvasive techniques that are free of ionizing radiation has riveted the attention of modern medicine because knowledge of the size of the heart's anatomic parts provides powerful diagnostic and therapeutic information. Dr. Nelson B. Schiller a member of the Department of Medicine, Cardiology Division, CVRI and John J. Sampson-Lucie Stern Endowed Chair in Cardiology, has spent his career investigating the application of echocardiography to the precise measurement and clinical application of the volume, weight and hemodynamics of the chambers and valves of the heart. His work is currently centered on the Heart and Soul Study (Mary Whooley, MD PI), where echocardiography measurements are being related to outcomes of heart disease.

Deepak Srivastava, M.D.
Director and Professor

Research Interests:
Developmental biology, pediatric cardiology, congenital heart defects, organogenesis, human genetics, stem cells, cardiac repair

Summary:
Dr. Srivastava's work focuses on understanding cardiac development by elucidating the molecular events regulating early and late developmental decisions that instruct progenitor cells to adopt a cardiac cell fate and subsequently fashion a functioning heart. This foundation has been used to discover the genetic basis for some congenital heart malformations.

Vasanth Vedantham, M.D., Ph.D.
Assistant Clinical Professor

Research Interests:
Development and function of the cardiac conduction system; molecular regulation of cardiac pacemaker cells; mechanisms of cardiac arrhythmias

Summary:
Our lab is focused on cardiac pacemaker cells, specialized cardiomyocytes whose autonomous electrical activity allows the sinoatrial node to serve as the heart's natural pacemaker. Specific questions include: How are pacemaker cells different from regular heart cells at the level of gene expression and regulation? How does their unique gene expression signature confer their distinctive electrophysiological properties? How have selection pressures generated functional differences in pacemaker cells among different vertebrate species? What are the molecular mechanisms that guide pacemaker cells to integrate electrically with the rest of the heart to form a node? How do pacemaker cell biology and function change in response to physiological and pathological stress? What is the mechanistic link between sinus node dysfunction and atrial fibrillation? Our approaches include mouse genetics, whole-animal and ex-vivo electrophysiology, cellular and molecular electrophysiology, gene expression analysis, and bioinformatics. Ultimately, we hope to design novel treatments for patients suffering from heart rhythm disorders, including sinus node dysfunction and atrial fibrillation

Rong Wang, Ph.D.
Professor

Research Interests:
Molecular Regulation of Mammalian Arterial Venous Specification

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.

Zena Werb, Ph.D.
Professor and Vice Chair

Research Interests:
Extracellular communication in development and disease

Summary:
The cellular microenvironment provides cells with information essential for controling development , cell-specific fate determination, gain or loss of tissue-specific functions, cell migrations, tissue repair and cell death. We are studying the role of the microenvironment in controlling embryonic development, mammary gland and bone development and tumorigenesis. Our interests include the critical roles that the ECM, inflammatoryand innate immune cells, vascular development and angiogenesis and degradative enzymes such as the matrix metalloproteinases play in these processes. We are taking genetic and molecular approaches to determine the identity and function of the critical molecules, how their expression and activities are regulated, what the molecular and cellular targets of these genes are, and how these regulate the signaling pathways. We are studying how a developing vascular system regulates bone formation, breast development and tumor growth. For example, we have found that tumor cells metastasize in regions of the tumor where blood vessels are abnormal and where there are abundant inflammatory cells. We want to understand the temporal, spatial and causal relationship between these three compartments, and whether targeting the tumors cells, blood vessels or the inflammatory cells, or all of them can slow down metastasis.

Ann C Zovein, M.D,
Assistant Professor

Research Interests:
Vascular development, diversity of endothelial lineages, vascular contributions to stem cell niches including hematopoietic stem cell emergence

Summary:
While at first glance it may appear that the blood vessels throughout the body have similar properties and functions, on closer examination vessels that comprise diverse vascular beds may arise from distinct origins and have unique potential and pathology. We investigate, from a developmental perspective, what makes arterial endothelial subsets unique… is it their location? or developmental history? And do these properties predict their future? i.e. propensity for disease.

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