CURRENT RESEARCH PROJECTS
Research projects in the lab generally center around developmental biology and/or environmental toxicology. A common thread is our interest in the plasma membrane, and in understanding how this membrane is adapted to perform diverse functions from signaling to protection to cell motility.
We have primarily focused on proteins called “transporters” that control the movement of small molecules across the plasma membrane. Transporters perform diverse functions from distribution of signaling molecules within a developing embryo, to limiting the uptake of pollutants. One of the families of transporters we are studying are the ABC (ATP-binding cassette) transporters. This is a large (typically >50 genes in deuterostomes), conserved family of membrane proteins encoding proteins that transport lipids, ions, signaling molecules and xenobiotics across membranes.
A second major interest in the lab is to understand how natural and anthropogenic chemicals gain entry into cells and why some chemicals are more persistent within cells than others. Traditional approaches to this problem focus on understanding the physical and chemical properties of chemicals that govern their fate in the environment or tendency to cross cell membranes. We approach the problem of persistence from the perspective of the cell by understanding the cell biological mechanisms, such as efflux transport, that lead to unexpected patterns of accumulation.
1. Primordial germ cells:
Industrial pollutants are pervasive in the environment and in humans. Legacy and emerging pollutants including flame retardants, pesticides, plasticizers, polyaromatic hydrocarbons, personal care products, are routinely detected in humans. Of concern is that these compounds, and their metabolites, are also routinely found in cord blood and amniotic fluid, indicating early life exposure. A vulnerable window of development is during formation and migration of the primordial germ cells (PGCs), the embryonic precursors of eggs and sperm. PGCs formation involves intense intercellular signaling events and dramatic epigenetic reprogramming events, that are vulnerable to the interfering effects of environmental chemicals. Importantly, PGCs are formed early in development and thus the innate cellular defenses of the PGC are critical for protection. The overall goal of this research is to understand how the primordial germ cell protects itself against xenobiotics, and to determine how the program of PGC development can render this cell vulnerable to the effects of real-world chemical mixtures.
2. Plasma membrane reorganization in embryo development and developmental functions of transporters:
Cell surfaces are dynamic. During embryonic development they undergo dramatic changes in structure and function coincident with changes in cell fate and function. The structural changes include changes in cell polarity, organization of cortical actin, insertion and removal of plasma membrane and exocytic deposition of extracellular matrix. The functional changes include changes in membrane transport and changes in receptivity to developmental and environmental signals. Our goal is to understand investigate how these structural and functional processes of membrane organization are intertwined. We have also recently shown that changes in surface expression of transporters can be essential for adapting cells to secret certain developmental signals.
3. Molecular interactions of persistent pollutants with ATP Binding Cassette transporters and “Transporter Interfering Chemicals” :
Complex mixtures of environmental chemicals are present in the environment including polyaromatic hydrocarbons, polychlorinated biphenyls, phthalates, bisphenol-A and pesticides — as well as the products of their maternal metabolism. A gap in knowledge exists with regard to our understanding of the interactions of these environmental chemicals with the repertoire of ATP Binding Cassette (ABC) and Solute Carrier (SLC) transporters important for protection of embryos. We work in collaboration with Dr. Geoffrey Chang, here at UCSD, to determine the interactions of these drug transporters with environmental compounds. This work has led to the first co-crystal structure of transporter bound to an environmental compounds. We have also discovered a new class of compounds, which we term Transporter Interfering Compounds (TICs) that can bind and inhibit this transporter.We are investigating how these impact the transporter defense system.
4. Development of low-cost pollutant sensors:
A myriad of environmental chemicals were released into the environment over the last century and these industrial chemicals are detected from the depths of the oceans to the poles of the earth and in the bodies of all humans on the planet. Many of these chemicals are well known toxicants, with particularly adverse health effects on human neonates and infants. To reduce our exposure to these chemicals, there is need for a feasible and affordable technique to monitor and estimate levels of these chemicals in our environment and food.
We are developing low cost molecular diagnostics to measure contaminants in different media, including water, meat, vegetables, dairy products, breast milk, and other food sources. These “dipsticks” are analogous to common pregnancy tests and will allow both researchers and novice users to quickly detect pollutants they are exposed to through diet.