- Research Assistant Professor, University of Notre Dame
- Assistant Research Professor, University of South Florida
- Research Associate, University of South Florida
- Postdoctoral Scholar, Memorial Sloan-Kettering Cancer Center
- Ph.D. in Neuroscience, University of South Florida
- M.S. in Pharmacology, University of South Florida
- B.S. in Microbiology, University of South Florida
- B.A. in Chemistry, University of South Florida
The Koren lab is a multidisciplinary group that integrates biochemistry, molecular biology, and biophysics to study diseases of protein aggregation, neurodegeneration, and cancer. Primarily, our work focuses on the activity and regulation of molecular chaperones. Molecular chaperones are the quality control system of living cells. Dysregulation or aberrant activity of molecular chaperones can drive the underlying pathology in diseases such as Alzheimer’s disease, post-traumatic stress disorder, glaucoma, and cancer.
Current and Funded Projects
Untangling Alzheimer’s Disease: Genetics, aberrant cell signaling, and cellular stressors lead to the neuronal accumulation of the tau protein. The accumulation of tau induces a shift from innocuous monomeric tau species into toxic soluble tau oligomers. Eventually, these oligomeric species form the insoluble neurofibrillary tangles observed upon autopsy. We have identified a family of proteins that present an enzymatic activity which can twist the tau species at distinct amino acids. Depending on the specific isomerase, the resulting tau can have enhanced toxicity or be shifted from an insoluble to soluble state. By studying the structures produced by these isomerization events, as well as the regulatory underlying biology, we hope to gain insight into what causes some, but not all, tau species to become toxic AND if isomerization has therapeutic potential.
Profiling Cancer: Oncogenic mutations alter the survival mechanisms of cancer cells. The diminished capacity of a cancer cell to undergo apoptosis limits the efficacy of targeted therapeutic strategies and increases the probability of refractory and resistant cancer cell populations. Our goal is to identify and profile the ‘survival addictions’ of individual cancer cells. Once profiled, we generate distinct and personalized combination therapeutic strategies to enhance the effect of targeted therapeutics by ablating the survival addictions unique to a cancer cell population.
Therapeutics for open angle glaucoma: Glaucoma is the leading cause of vision impairment and blindness in the world. Mutations in the myocilin gene cause glaucoma in ~100,000 United States citizens alone. These mutations cause myocilin to accumulate in the trabecular meshwork – a region necessary for maintaining the internal pressure in the eye. We have discovered that selective inhibitors of the molecular chaperone Grp94 can eliminate mutant myocilin and the damage caused by the resulting elevated ocular pressure. We are working to improve the efficacy of Grp94 inhibitors and to evaluate the potential of Grp94 inhibitors to treat additional forms of glaucoma.
- Sabbagh, J.J., Cordova, R.A., Zheng, D., Criado-Marrero, M., Lemus, A., Li, P., Baker, J.D., Nordhues, B.A., Darling, A.L., Martinez-Licha, C., Rutz, D.A., Patel, S., Buchner, J., Leahy, J.W., Koren, J., Dickey, C.A., Blair, L.J. "Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD" 2018 ACS Chemical Biology, 13 (8), pp. 2288-2299. DOI: 10.1021/acschembio.8b00454
- Huard, D.J.E., Crowley, V.M., Du, Y., Cordova, R.A., Sun, Z., Tomlin, M.O., Dickey, C.A., Koren, J., III, Blair, L., Fu, H., Blagg, B.S.J., Lieberman, R.L. "Trifunctional High-Throughput Screen Identifies Promising Scaffold to Inhibit Grp94 and Treat Myocilin-Associated Glaucoma" 2018 ACS Chemical Biology, 13 (4), pp. 933-941. DOI: 10.1021/acschembio.7b01083
- Criado-Marrero, M., Rein, T., Binder, E.B., Porter, J.T., Koren, J., III, Blair, L.J. "Hsp90 and FKBP51: Complex regulators of psychiatric diseases" 2018 Philosophical Transactions of the Royal Society B: Biological Sciences, 373 (1738), 20160532. DOI: 10.1098/rstb.2016.0532
- Shelton, L.B., Koren, J., III, Blair, L.J. "Imbalances in the Hsp90 chaperone machinery: Implications for tauopathies" 2017 Frontiers in Neuroscience, 11 (DEC), 724. DOI: 10.3389/fnins.2017.00724
- Stothert, A.R., Suntharalingam, A., Tang, X., Crowley, V.M., Mishra, S.J., Webster, J.M., Nordhues, B.A., Huard, D.J.E., Passaglia, C.L., Lieberman, R.L., Blagg, B.S.J., Blair, L.J., Koren, J., III, Dickey, C.A. "Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma" 2017 Scientific Reports, 7 (1), 17951. DOI: 10.1038/s41598-017-18344-4
- Shelton, L.B., Baker, J.D., Zheng, D., Sullivan, L.E., Solanki, P.K., Webster, J.M., Sun, Z., Sabbagh, J.J., Nordhues, B.A., Koren, J., III, Ghosh, S., Blagg, B.S.J., Blair, L.J., Dickey, C.A. "Hsp90 activator Aha1 drives production of pathological tau aggregates" 2017 Proceedings of the National Academy of Sciences of the United States of America, 114 (36), pp. 9707-9712. DOI: 10.1073/pnas.1707039114