Pharmaceutical Sciences Seminar Series

2020 Pharmaceutical Sciences Seminar Series

Every Wednesday at 12pm PT via Zoom

Title

A Unifying Molecular Mechanism for Anesthesia and Mechanosensation 

Abstract

Anesthetics are used every day in thousands of hospitals to induce reversible loss of consciousness. For 100 years scientists speculated anesthetics could target the plasma membrane, but no direct proof emerged. I will discuss data that show anesthetics directly act on a subset of plasma membrane to activate an ion channel TREK-1.  Using super resolution imaging, electrophysiology, and in vivo data in a fruit fly, I will describe a membrane mediated mechanism of anesthesia and its intersection with mechanosensation. 

Title

Membranes and Amphiphiles: Probing Roles Beyond Compartmentalization with All Atom Simulations

Abstract

Membranes are increasingly recognized not only for the role in localization, but also in the regulation of cellular activities. In this talk I will describe our efforts to understand the physical driving forces behind membrane permeation, organelle trafficking, and lipid droplet protein targeting with all atom molecular dynamics simulations. The first story queries mycolactone, a seemingly simple amphiphilic toxin that induces necrosis by inhibiting membrane proteins and cell adhesion while also blocking pain and inflammation. Originally thought to passively diffuse through membranes, our simulations reveal strong and organelle-specific membrane association that helps to explain several aspects of the toxin’s pathogenicity. The second story delves into lipid droplets, energy storage organelles with a phospholipid monolayer as opposed to bilayer. Our simulations suggest new perspectives on the surface and hydration properties of lipid droplets as well as patterns and interactions that drive protein recruitment.

Title

Reconfiguring Ribosomes During and After Assembly


Abstract

Ribosomes produce protein in all cells. In doing so, they must faithfully translate the mRNA sequence into protein and interpret other instructions in the mRNA to maintain protein homeostasis via differential translation initiation rates, and by modulating elongation and termination efficiencies. Failure to accurately interpret the instructions that specify protein sequence or levels leads to pathologies, including cancer. Our work has shown that “specialized” ribosomes, lacking individual ribosomal proteins, accumulate both under physiological as well as pathological cellular situations. These ribosomes divert the normal translational program, which can modulate the stress response. Using the information from high throughput sequencing and luciferase reporter assays, we can re-program entire cellular pathways to make them responsive to stress-induced changes in ribosome composition. Excitingly, computational analysis of natural yeast isolates demonstrates that these changes also occur during adaptation, suggesting that specialized ribosomes provide a facile route for evolution. Finally, we provide a mechanism by which cancer cells disrupt mechanisms that ensure stoichiometric assembly of ribosomal proteins into the small subunit head in normal cells, to produce heterogeneous ribosomes, which endow the cells with stress resistance, but also unique vulnerabilities.

Title 

Mass Spectrometry as a Tool for Studying Ovarian Cancer Screening

Abstract

Ovarian cancer (OC) is the deadliest form of gynecological malignancy representing the fifth leading cause of cancer-related deaths among women. High-grade serous ovarian cancer (HGSOC) is the most common and lethal OC subtype, responsible for 70%-80% of these deaths. Due to nonspecific symptoms and a lack of early detection strategies, the majority of women with HGSOC are diagnosed at a late stage when the five-year survival rate can be as low as 17%.8. This five-year survival rate has remained unchanged since the1980s, highlighting the urgent need to investigate the molecular events underlying HGSOC pathogenesis and develop tools for routine screenings in women’s wellness exams. To help address these urgent needs, we have adapted our imaging mass spectrometry (IMS) platform to visualize chemical communication in the primary metastasis of ovarian cancer. We have also begun to study microproteins from vaginal samples as a fingerprint for studying disease progression.

Title

Methods to Evaluate and Perturb the Activity of the Human Proteasome with Small Molecules

Abstract

The degradation of proteins is an essential cellular process. The proteasome, a multi-catalytic enzyme, is mainly responsible for degrading proteins that are no longer required by the cell. My lab has focused on the development of activity probes that can monitor real-time proteasome activity biochemically and in live cells. These probes can be applied in variety of analytical methods including confocal microscopy, flow cytometry, and fluorescent plate readers. With these probes, we have discovered a variety of proteasome stimulators and binders to non-catalytic subunits. The recently discovered proteasome stimulators have been applied to determine the effects of increasing the ubiquitin-independent degradation of proteins. Moving forward, we are now analyzing how these small molecule stimulators can affect the accumulation of unwanted proteins, including alpha-synuclein.

Title

New 3D Culture Tools to Quantify Oxygen’s Role in Tissue Homeostasis and Cancer Progression 

Abstract

Oxygen is a master regulator of many cellular processes. There is no single oxygen tension in tissues but a gradient that extends radially outward from the blood vessel due to cellular consumption outpacing mass transport. These gradients become exaggerated during ischemic events or in poorly vascularized solid tumors and are thought to be a driving force in disease progression. Despite the complexity of the tissue microenvironment, many in vitro studies continue to disregard the role of oxygen, culturing cells at atmospheric oxygen levels. In this talk, I will highlight the tools our lab is developing to address three long-standing questions in tumor biology, each of which is fundamentally related to tissue-level oxygenation. First is oxygen’s role in directing cellular movement. Second is oxygen’s role in promoting drug resistance. The third is the relationship between hypoxia and hormone responsiveness in estrogen receptor alpha positive (ER+) breast cancers. 

Title

Versatile Perfluorocarbon Nanoemulsions Stabilized by Poly(2-oxazoline) Amphiphiles

Abstract

Perfluorocarbon (PFC) nanoemulsions are non-toxic, dynamic nanomaterials that have been previously employed as oxygen carriers and contrast agents. We leverage the orthogonal nature of the fluorous phase to, in one step, prepare multifunctional nanomaterials with fluorous-tagged therapeutics loaded on the inside and targeting agents on the outside. We have shown that the retention of the payload inside the nanoemulsions can be controlled by the fluorous tags and the choice of surfactant. The surfactant also dictates the size, stability, and surface chemistry of the droplets. We have explored poly(2-oxazoline) surfactants to stabilize the PFC nanoemulsions, which provide many advantages over existing surfactants including their chemical modification to control cellular uptake, target specific epitopes, and trigger cargo release. This presentation will highlight the development and applications of PFC nanoemulsions stabilized with poly(2-oxazoline)s.  

Title

Development of Novel Materials and Sensing Electrodes for Biomedical Applications

Abstract

Materials science has played an enormous role in the success of medical devices and drug delivery systems. My research aims at studying the fundamental aspects of a broad range of materials, designing, synthesizing, and fabricating novel functional materials and exploring their biomedical and biological applications. In this talk, I will first discuss my previous work, where we prepared various materials including nanoparticles, dendrimers, conducting polymers, and polymeric mediators for biosensing electrode fabrication, drug delivery, and tissue engineering applications. I will then discuss my work at UC Irvine, where we developed novel biosensors for monitoring neurotransmitters. They are essential for human health, and any imbalance in their activities can cause serious mental disorders such as Parkinson’s disease, schizophrenia, and Alzheimer’s disease. Monitoring neurotransmitters such as dopamine, noradrenaline, and glutamate is of great importance in studying and diagnosing neurological and psychiatric disorders such as Parkinson’s disease, schizophrenia, and Alzheimer’s disease. Electrochemical detection techniques have been paving the path in this direction for more than four decades now. To develop an electrochemical biosensor for monoamine neurotransmitters, we explore the use of unique materials for developing biosensors for in vitro, in vivo, and ex vivo models.  

Contact: Sppscomm@uci.edu