Projects

Current

Membrane science at the interface of virology and engineering

Polymer membranes are well established as powerful tools in a variety of areas, from water purification to production of advanced biologic drugs like antibodies. Hollow fiber membranes are particularly useful for applications requiring high throughput since they pack high surface areas into small volumes; air filtration is a prime example of an application that necessitates large volume separations. In my project, I've brought together virologists and engineers to show that hollow fiber membranes (like the Lifestraw membrane that is cheap and easily available) can be used to remove airborne virus particles like the SARS-CoV-2 virus that causes COVID-19 (and other small particulate matter that contributes significantly to the global burden of disease). Ongoing work involves studying how we can functionalize membrane materials to further advance their applications in improving air quality.

Past

Antibody design for targeting oncogenic HER2 ectodomain mutants

HER2 is a cell surface protein and member of the endothelial growth factor receptor (EGFR) family. HER2 has been found to be a driver in a variety of cancer types, most notably about 25-30% of all breast cancers that overexpress HER2. In these overexpressing cancers, antibody therapy targeting HER2 has been quite effective, but a smaller subset of breast cancers are driven by mutations in HER2 rather than its overexpression. Some of these mutations actually wind up right at the site of targeting by antibodies like Pertuzumab, so my project was studying how we can use in vitro and in silico methods to re-engineer these antibodies to target the mutated cell surface proteins like HER2. 

Understanding the role of post-transcriptional modifications in noncoding RNA function

The four basic RNA letters (AGCU) with
two of the >140 examples of  modifications
that are known to occur 

Since I started as a graduate student, I've been fascinated by how the four basic RNA letters can be edited by cellular machinery to fine tune the function of (especially ribosomal and transfer) RNAs. Through my effort of writing a review, I learned how important RNA modification to a variety of noncoding RNAs involved in translation and splicing. I was most interested in how cells can tweak the function of their ribosomes to help them survive stresses like heat shock or oxidative stress, simply by adding a chemical group. These changes can alter how proteins are translated, or stabilize important structures in the ribosome, or a number of other mechanisms for engaging cellular stress responses.

Reprinted with permission from Baldridge, K. C. et al. 
Directed Evolution of Heterologous tRNAs Leads to Reduced 
Dependence on Post-transcriptional Modifications. ACS Synth. Biol. 7, (2018).
Copyright 2018 American Chemical Society

I became interested in studying how native transfer RNA modifications play a role in efforts to expand the genetic code (GCE) using engineered orthogonal translational machinery. Using tRNA from another organism allows addition of a new amino acid to the canonical 20 aa code, but it's pretty common to have problems like poor yields or growth rates. To help improve this approach, we examined how RNA modifications from native machinery might affect the function of non-native tRNAs in the cell. This work showed that the efficiency of orthogonal tRNAs within the host translational machinery (including post-transcriptional modification enzymes) is a critical feature of the best candidates. Highly abundant non-native tRNAs can throw a wrench in the works of native tRNA modification machinery and change host tRNA modification patterns.

Effects of simulated air pollution mixtures on RNA biochemistry

When we walk down the street in a bustling city or an industrial area, we are constantly bombarded with toxic components of air pollution. From a public health perspective, understanding how these exposures contribute to development of diseases is critical to reduce rates of overall mortality and cardiovascular disease. In my past work, we found that oxidative stress caused by exposure of human epithelial cell lines grown to mimic the first layer of contact in the lungs altered the chemistry of RNA, namely oxidizing guanine to 8-oxoguanine (8OG). Based on this earlier work, I expanded the investigations into mapping the sites of 8OG in cellular RNAs while developing new protocols for how to accomplish this. These results and further development efforts by my colleague in the Contreras lab, Juan Gonzalez-Rivera, have been used to identify functional consequences of RNA oxidation caused by simulated air pollution exposures.