Category: Research Area


Deepak Srivastava, M.D.

Srivastava

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.

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Matthew L Springer, Ph.D.

 

Matt 2016

Research Interests:
Angiogenesis, VEGF, stem cells, progenitor cells, gene therapy, heart failure, myocardial infarction, coronary artery disease, cardiac regeneration, peripheral artery disease, vascular injury, nitric oxide, flavanols, skeletal muscle myoblasts, secondhand smoke

Summary:
Our research interests include cell therapy and gene therapy approaches to studying cardiovascular disease, with the goals of exploring potential treatments and understanding underlying mechanisms involved in angiogenesis, vascular function, and treatments for myocardial infarction. The laboratory is studying the effects of VEGF and pleiotrophin gene therapy on the heart and limb vasculature in mice. Further interests center in the therapeutic effects of ultrasound-guided bone marrow cell implantation into the heart after myocardial infarction, with a special emphasis on the therapeutic implications of the age and cardiac disease state of the cell donor. Similarly, the lab is studying the effects of age and disease on circulating angiogenic cells (sometimes called endothelial progenitor cells), with a focus on the roles of endothelial nitric oxide synthase and nitric oxide in the function of these cells. Lastly, they have developed a rat model of endothelium-dependent flow-mediated vasodilation, and are using it to examine mechanisms underlying vascular reactivity and how they are affected by cigarette smoke exposure.

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Anthony K Shum, M.D.

Shum

Research Interests:
Autoimmune lung disease, interstitial lung disease, ER stress, lung injury, lung fibrosis, lung autoantigens

Summary:
The Shum lab is interested in understanding the immune mechanisms that lead to lung inflammation and fibrosis in patients with autoimmune disorders. Through human and mouse studies, we seek to define the critical factors that lead to autoimmune lung disease in order to speed the development of diagnostic tests and treatments for patients.

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Xiaokun Shu, Ph.D.

Shu

Research Interests:
Protein Rational Design and Directed Evolution for Biology and Medicine

Summary:
We are developing technologies to bridge the gap between clinical medicine and molecular biology. Their successful use in biomedicine will significantly improve treatment of disease.

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Dean Sheppard, M.D.

Sheppard

Research Interests:
In vivo function of integrins and molecular basis of lung diseases

Summary:
Dean Sheppard’s laboratory studies how cells respond to and modify their surroundings using receptors called integrins. They have found important roles for integrins in lung and kidney fibrosis, septic shock, acute lung injury, asthma and stroke and are testing drugs targeting integrins in animal models and in people affected by these diseases.

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Nelson B Schiller, M.D.

Schiller

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.

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

Reiter

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.

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Rita F Redberg, M.D., M.Sc.

Redberg

Research Interests:
Summary:
Dr. Rita F. Redberg’s research interests are non-invasive imaging of the coronary arteries comparing transesophageal echo with ultrafast CT and magnetic resonance imaging. Her ongoing research studies include a stray of the role of exercise in heart disease in women. She also does research in exercise echo evaluation of valvular and congenital heart disease as well as the use of transesophageal echo imaging in cardiopulmonary resuscitation.

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Jeffrey E Olgin, M.D.

Olgin

Research Interests:
Cardiac Electrophysiology, Arrhythmias, Mechanisms, Remodeling, Cardiac Fibrosis, Atrial Fibrillation, Cardiac Ablation, Mouse models, animal models, mouse electrophysiology, optical mapping, atrial fibrillation ablation, clinical trials.

Summary:

Mechanisms of arrhythmias, remodeling and cardiac fibrosis, atrial fibrillation, ventricular fibrillation, sudden death, prediction of atrial fibrillation, prediction of sudden death.
Dr. Olgin’s basic research lab is interested in atrial and ventricular remodeling and how these processes occur to develop a substrate for atrial fibrillation and ventricular tachycardia. His work has demonstrated the circuit for human atrial flutter and has demonstrated the importance of atrial fibrosis as a cause for atrial fibrillation. He is currently interested in how TGFß signaling is regulated in the atria to produce atrial fibrosis and atrial fibrillation. His lab is translational in that he utilizes a spectrum of techniques and studies that span from mouse, large animal physiologic models, human tissue, human biomarkers and genetic approaches to understanding the disease. He also has active studies in understanding the remodeling that occurs in the ventricle in the setting of heart failure and myocardial infarction to create the substrate for sudden death and ventricular tachycardia and fibrillation.
Dr. Olgin also runs the UCSF Cardiology Clinical Coordinating Center. He is PI of the VEST study, a multi-center, international randomized study to determine whether a wearable defibrillator vest can reduce the big early sudden death rate post-MI.

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

Mostov

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.

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