Research Interests:
Gene regulatory networks, machine learning, and cardiovascular disease
Summary:
Our lab studies how genes interact within networks to direct normal heart development and how those networks are disrupted in cardiovascular disease. Using a combination of computational and experimental approaches, we map the disrupted gene networks to enable the design of therapies that correct them back to the healthy state.
Research Interests:
Systems biology, quantitative unbiased approaches, proteomics, genetic interactions, proteinprotein interactions, post-translational modifications, cancer, infectious diseases, cardiac development, psychiatric disorders.
Summary:
Our research focuses on fundamental biological mechanisms, because cures to many diseases have been revealed by unexpected discoveries in the basic sciences. We use and develop complementing technologies that allow the unbiased study of the cell. We create maps to study how proteins work together in cells, and how this changes during different diseases, including infectious diseases, cancer as well as neurological and psychiatric disorders. We strongly believe that impactful research is accomplished when diverse groups of scientists work together, and therefore we are working in close collaboration with national and international experts from different disciplines on all of our projects.
Research Interests:
Tobacco control, health policy, nursing, public health, capacity building, smoking cessation, cancer, non-communicable diseases, tobacco industry, global health, health diplomacy, sustainable development goals.
Summary:
Dr. Stella Bialous’ research focuses on the WHO Framework Convention on Tobacco Control, tobacco industry monitoring and building nurses’ capacity for tobacco control nationally and internationally. Dr. Bialous has consulted with the World Health Organization’s Tobacco Free Initiative for over 15 years. In 2003, she received the American Legacy Foundation’s Sybill G. Jacobson Adult Award for Outstanding Use of Tobacco Industry Document. In 2012, she received the International Society of Nurses in Cancer Care Distinguished Merit Award and is currently the Society’s President.
Developmental pathways in the maintenance of adult tissue homeostasis
Our laboratory is interested in studying how key developmental pathways continue to persist in adulthood to maintain normal homeostatic organ function. We are particularly focused on the mesenchymal cell types (e.g. fibroblasts, pericytes, and etc.) that are poorly understood and lack precise anatomical definition, but are integral to the structural integrity and function of adult organs such as the lung.
Five UC San Francisco faculty members have been elected to the American Society for Clinical Investigation (ASCI) after a highly competitive nomination process.
The ASCI, which is one of the oldest medical honor societies in the United States, received 160 membership nominations for 2016 and recommended 74 nominees for election.
The five faculty members elected are:
Pamela M. Ling, MD, MPH, a professor in the Department of Internal Medicine, studies tobacco industry marketing strategies targeting young adults, women, and other high-risk population, and new smokeless and novel tobacco product marketing strategies the UCSF Center for Tobacco Control Research and Education.
Research Interests:
Subcellular organization and dynamics of receptor-mediated signaling systems in eukaryotic cells.
Summary:
Our laboratory studies mechanisms by which receptors that control cardiovascular biology are regulated. These receptors are important therapeutic targets and their regulation is known to be disturbed in a number of important disease states.
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.
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.
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.
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.
Research Interests:
Molecular Genetics of Complex Disease, Genetic Models of Hypertension and the Metabolic Syndrome, Transcription Modulating Drugs
Summary:
Hypertension affects 30% of the population and is a major cause of stroke, kidney failure, and heart disease. Patients with hypertension are also at increased risk for diabetes. Our laboratory is studying genetic mechanisms that promote increased blood pressure with the goal of identifying new opportunities for the prevention and treatment of hypertension, diabetes, and cardiovascular disease.
Research Interests:
Summary:
Lipoprotein metabolism and risk of cardiovascular disease
Despite recent advances in treatment, cardiovascular disease (CVD) remains the leading cause of death in the US and will soon achieve this status globally. Our group’s research is aimed at addressing three major challenges for reducing this enormous disease burden. First, standard diagnostic procedures do not identify a high proportion of children and adults who are at risk for CVD. We have developed and implemented a sophisticated new procedure that, by analyzing individual lipoprotein particles, provides more specific information than that afforded by ordinary cholesterol testing, and hence is capable of improving both the assessment and management of CVD risk. Second, dietary and lifestyle guidance has failed to substantially impact CVD risk factors, particularly those related to overweight and obesity. We have demonstrated that carbohydrate restriction can reverse the high risk lipid profile found in a high proportion of overweight and obese individuals even without weight loss, and that this effect is independent of saturated fat intake. These findings have helped support dietary guidelines that place a greater emphasis on limiting refined carbohydrates than fats. Third, despite the awareness of wide interindividual variability in response to treatments aimed at reducing CVD risk, the potential benefits of applying genomic tools for developing personalized approaches for maximizing CVD risk reduction have not been realized. A major component of our research program has been the application and development of genomic methodology for dissecting genetic influences on the therapeutic responses to statins, the most widely prescribed class of drugs for reducing CVD risk.