Phone: 503 494-9359
Associate Professor, Biomedical Engineering
Assistant Professor, Physiology & Pharmacology
Collaborative Life Sciences Building
Mail code: CL3B
2730 SW Moody Avenue
Portland, OR 97201
Collaborative Life Sciences Building
Mail code: CL3B
Ph.D., Chemistry, California Institute of Technology, 2008
B.S., Biochemistry, University of California, 2002
OHSU Center for Spatial Systems Biomedicine
A focus of the Beatty Group at OHSU is developing new chemical tools for illuminating human diseases. We have been inspired to use innovative, cross-disciplinary approaches to identify and investigate the molecular basis of human diseases, including tuberculosis (TB) and breast cancer. Since 2012, we have worked on the following research projects:
Chemical tools for detecting hydrolase activities in Mtb
The human pathogen Mtb is the causative agent of tuberculosis (TB). TB is the deadliest disease in human history, and kills nearly 2 million people every year. We are creating new chemical tools and using them to make fundamental discoveries on Mtb hydrolases implicated in latent and active TB infections. To study TB pathogenesis, we use novel fluorogenic probes to reveal the activity of Mtb-associated hydrolases. Dormant Mtb has reduced metabolism and enzymatic activity, but hydrolases that remain active facilitate pathogen survival. Recently, we defined the esterase activity profiles associated with latent and active disease because latent TB is a major barrier to eradication. We hypothesized that Mtb would regulate esterase activity during the conversion from active replication to dormancy. To undertake these studies, we used both activity-based probes (ABPs) and fluorogenic esterase substrates (ACS Infectious Diseases, 2016). Both types of small molecule probes revealed functional esterases in active, dormant, and reactivating cultures. To summarize that work, we found that there is dynamic regulation of Mtb esterases during dormancy, reactivation, and active growth. This makes esterases excellent targets for classifying Mtb infections, and in the future such probes might be used to characterize TB patient lung lesions. Esterases with persistent activity are potential diagnostic biomarkers or therapeutic targets for Mtb-infected individuals with latent or active TB. In the future, we will continue to characterize hydrolases associated with various stages of infection.
A new technology for tracking and mapping proteins by light and electron microscopy
Recent advances in imaging instrumentation and computational analysis have created new opportunities for investigating the molecular basis of diseases with remarkable detail. It is now possible to interrogate features ranging in size from angstroms to centimeters, which enables investigations into tissue architectures, neuronal connections, organelle coordination, signaling networks, and molecular organization. These are representative examples of the types of studies that would immediately benefit from a versatile technology for labeling and tracking proteins across size scales. We foresee an increased reliance on multi-color, multi-scale microscopy for investigating proteins associated with human diseases. The central obstacle that has decelerated progress in this area is the shortage of methods for labeling proteins for multi-scale microscopy.
To address this unmet need, we created a new concept for labeling proteins with reporters compatible with multi-scale microscopy. Our strategy combines genetically-encoded peptide tags with a palette of reporter chemistries for labeling cellular nanostructures. In 2017, we published our first demonstration of using versatile interacting peptide (VIP) tags to label cellular proteins (ChemBioChem, 2017). In ongoing work, we are developing and validating additional VIP tags, which will be small, target specific, easy-to-use, customizable, and cell compatible. For example, we are now optimizing the VIPER tag, which introduces CoilE as a new tag for imaging cellular proteins at high resolution (manuscript in preparation, Jan. 2018). This project is currently funded by the NIGMS (R01 GM122854).
Imaging the HER signaling network in breast cancer
In a new project, our group is collaborating with Dr. Joe Gray and Dr. Jim Korkola to investigate mechanisms of drug resistance in breast cancer. HER2 amplification occurs in ~25% of all breast cancer and is associated with poor prognosis. HER2-targeted therapeutics are clinically available, but their efficacy in patients has not lived up to pre-clinical promise. Multiple reasons for resistance to HER2-targeted inhibitors have been identified, including reactivation of HER2 signaling through feedback mechanisms. HER2 is thought to require HER3 as a partner for oncogenic signaling, as knockout of HER3 phenocopies HER2 knockout in HER2-amplified cells. We are using VIP tags to capture multi-color views of the dynamics of HER2-HER3 signaling.
Synthesis of new fluorescent and fluorogenic probes
Many of the most widely used reporter chemistries are fluorescent or fluorogenic (e.g., "turn-on") probes. For imaging within living systems, the most useful fluorophores excite and emit between 600 and 800 nm. This region is biologically "quiet", with little endogenous absorption, scattering, or autofluorescence. However, there are few far-red chemical reporters. We are using our expertise in color chemistry to develop new fluorescent and fluorogenic probes. Some of our research in this area used the far-red fluorophore DDAO (Proc. Natl. Acad. Sci. USA 2013, ACS Chem. Biol. 2016, ACS Infect. Dis. 2016, ChemBioChem 2014). We have also synthesized far-red carbazines that can be converted into enzyme-activated fluorophores (Chem. Commun., 2016). In the future, we team will continue to develop novel molecular imaging agents for biomedical research.
- H.K. Zane*, J.K. Doh*, C.A. Enns, K.E. Beatty. "Versatile interacting peptide (VIP) tags for labeling proteins with bright chemical reporters." ChemBioChem 18(5), 470-474 (2017).
- K.R. Tallman, S.R. Levine, K.E. Beatty. "Small-Molecule Probes Reveal Esterases with Persistent Activity in Dormant and Reactivating Mycobacterium tuberculosis." ACS Infect. Dis. 2(12), 936-944 (2016).
- K.R. Tallman, S.R. Levine, K.E. Beatty. "Profiling Esterases in Mycobacterium tuberculosis Using Far-Red Fluorogenic Substrates." ACS Chem. Biol. 11(7), 1810-1815 (2016).
- S.R. Levine, K.E. Beatty. "Synthesis of a far-red fluorophore and its use as an esterase probe in living cells." Chem. Commun. 52, 1835-1838 (2016). DOI 10.1039/C5CC08764 K.R. Tallman, K.E. Beatty. "Far-Red Fluorogenic Probes for Esterase and Lipase Detection." ChemBioChem 16(1), 70-75 (2015).
- E.L. Smith, C.R. Bertozzi, K.E. Beatty. "An Expanded Set of Fluorogenic Sulfatase Activity Probes." ChemBioChem, 15(8), 1101-1105 (2014).
- K.E. Beatty, M. Williams, B.L. Carlson, B.M. Swarts, R.M. Warren, P.D. van Helden, C.R. Bertozzi. "Sulfatase-activated fluorophores for rapid discrimination of mycobacterial species and strains." Proc. Natl. Acad. Sci. USA, 110(32), 12911-12916 (2013).
More publications available on PUBMED: Kimberly Beatty
The Beatty Lab is always looking for talented researchers to join the group. To apply for a post-doctoral research position, submit a cover letter, CV, and a copy of two representative publications to beattyk [AT] ohsu (dot) edu. In the cover letter, please describe what type of project you would like to pursue in the Beatty Lab and why you are uniquely qualified for this position. The cover letter should also describe your research experience, particularly in chemical biology and imaging. Currently, we are recruiting postdoctoral scholars in this research area: genetically-encoded tags for multi-color, nanoscale imaging.