Ku-Lung Hsu

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Primary Appointment

Associate Professor, Chemistry

Research Description

Professor Hsu is an Associate Professor in the Departments of Chemistry and Pharmacology at the University of Virginia. The Hsu Lab is focused on developing chemical methods and probes to address fundamental challenges associated with studying regulation of metabolism and signaling in vivo. Current efforts are focused on discovery of new lipid metabolic targets for chronic inflammation and immuno-oncology. Members of the Hsu Lab receive cross-disciplinary training in chemical biology, mass spectrometry, medicinal chemistry, and in vivo pharmacology. Professor Hsu is a recipient of several awards including the highly competitive NIH K99/R00 Pathway to Independence Award, DOD CDMRP Career Development Award, a Young Investigator Award from the Melanoma Research Alliance (MRA), NSF CAREER Award, and the Emerging Leader Award from The Mark Foundation for Cancer Research.

Personal Statement

Dr. Hsuâs research interests are in developing and applying chemical- and mass spectrometry-based technologies to study metabolic regulation and function in vivo, with a special emphasis on lipid signaling pathways in inflammation and immunity. Dr. Hsuâs research has led to the development of selective, in vivo-active small-molecule inhibitors and chemical probes targeting bioactive lipid networks in macrophages. His recent work has focused on high-throughput screening (HTS) approaches to identify novel small molecule inhibitors to study the pro-tumorigenic functions of poorly-annotated metabolic enzymes implicated in cancer pathogenicity. Using a fluorescence polarization assay to screen the NIH 300,000+ compound library, his group identified potent, selective, and reversible inhibitors of platelet-activating factor acetylhydrolases that blocked the survival of human cancer cell lines. Dr. Hsu aims to learn how the immunosuppressive tumor microenvironment directs or supports immune dysfunction in cancer to guide development of small molecules to enhance anti-tumor immunity. Dr. Hsu currently supervises 3 graduate students, 2 research scientists, and 3 undergraduate students in his laboratory. Dr. Hsu is interested in establishing an interdisciplinary research environment to promote scientific as well as personal development in the chemical and biological sciences. By interfacing graduate and undergraduate students in collaborative projects, Dr. Hsu aims to provide students in his group an opportunity to gain mentoring experience. Undergraduate students in his group are encouraged to work on independent projects with the goal of presenting their findings in written and oral format as part of the Distinguished Majors Program in the Chemistry department at UVa.

Training

  • Biotechnology Training Grant
  • Cancer Research Training in Molecular Biology
  • Predoctoral Training in Neuroscience
  • Training in Molecular Biophysics
  • Training in the Pharmacological Sciences

Selected Publications

2020

Ware, T. B., Franks, C. E., Granade, M. E., Zhang, M., Kim, K. -B., Park, K. -S., . . . Hsu, K. -L. (2020). Reprogramming fatty acyl specificity of lipid kinases via C1 domain engineering. NATURE CHEMICAL BIOLOGY, 16(2), 170-+. doi:10.1038/s41589-019-0445-9

Yin, B., Mendez, R., Zhao, X. -Y., Rakhit, R., Hsu, K. -L., & Ewald, S. E. (2020). Automated Spatially Targeted Optical Microproteomics (autoSTOMP) to Determine Protein Complexity of Subcellular Structures. ANALYTICAL CHEMISTRY, 92(2), 2005-2010. doi:10.1021/acs.analchem.9b04396

Brulet, J. W., Borne, A. L., Yuan, K., Libby, A. H., & Hsu, K. -L. (2020). Liganding Functional Tyrosine Sites on Proteins Using Sulfur- Triazole Exchange Chemistry. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 142(18), 8270-8280. doi:10.1021/jacs.0c00648

Shin, M., Ware, T. B., & Hsu, K. -L. (2020). DAGL-Beta Functions as a PUFA-Specific Triacylglycerol Lipase in Macrophages. CELL CHEMICAL BIOLOGY, 27(3), 314-+. doi:10.1016/j.chembiol.2020.01.005

2019

Hahm, H. S., Toroitich, E. K., Borne, A. L., Brulet, J. W., Libby, A. H., Yuan, K., . . . Hsu, K. -L. (2020). Global targeting of functional tyrosines using sulfur-triazole exchange chemistry. NATURE CHEMICAL BIOLOGY, 16(2), 150-+. doi:10.1038/s41589-019-0404-5

Yin, B., Mendez, R., Zhao, X., Rahkit, R., Hsu, K. -L., & Ewald, S. (2019). Automated Spatially Targeted Optical Micro Proteomics (autoSTOMP) to determine protein complexity of subcellular structures. doi:10.1101/783340

Franks, C. E., & Hsu, K. -L. (2019). Activity-Based Kinome Profiling Using Chemical Proteomics and ATP Acyl Phosphates.. Current protocols in chemical biology, 11(3), e72. doi:10.1002/cpch.72

Ware, T. B., Shin, M., & Hsu, K. -L. (2019). Metabolomics analysis of lipid metabolizing enzyme activity. POST-TRANSLATIONAL MODIFICATIONS THAT MODULATE ENZYME ACTIVITY, 626, 407-428. doi:10.1016/bs.mie.2019.06.027

Lazo, J. S., Blanco, I. K., Tasker, N. R., Rastelli, E. J., Burnett, J. C., Garrott, S. R., . . . Sharlow, E. R. (2019). Next-Generation Cell-Active Inhibitors of the Undrugged Oncogenic PTP4A3 Phosphatase. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 371(3), 652-662. doi:10.1124/jpet.119.262188

Shin, M., Buckner, A., Prince, J., Bullock, T. N. J., & Hsu, K. -L. (2019). Diacylglycerol Lipase-β Is Required for TNF-α Response but Not CD8+ T Cell Priming Capacity of Dendritic Cells. CELL CHEMICAL BIOLOGY, 26(7), 1036-+. doi:10.1016/j.chembiol.2019.04.002

2018

Borne, A. L., Huang, T., McCloud, R. L., Pachaiyappan, B., Bullock, T. N. J., & Hsu, K. -L. (2019). Deciphering T Cell Immunometabolism with Activity-Based Protein Profiling. ACTIVITY-BASED PROTEIN PROFILING, 420, 175-210. doi:10.1007/82_2018_124

Shin, M., Ware, T. B., Lee, H. -C., & Hsu, K. -L. (2019). Lipid-metabolizing serine hydrolases in the mammalian central nervous system: endocannabinoids and beyond. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1864(6), 907-921. doi:10.1016/j.bbalip.2018.08.007

Manterola, A., Bernal-Chico, A., Cipriani, R., Canedo-Antelo, M., Moreno-Garcia, A., Martin-Fontecha, M., . . . Mato, S. (2018). Deregulation of the endocannabinoid system and therapeutic potential of ABHD6 blockade in the cuprizone model of demyelination. BIOCHEMICAL PHARMACOLOGY, 157, 189-201. doi:10.1016/j.bcp.2018.07.042

Shin, M., Franks, C. E., & Hsu, K. -L. (2018). Isoform-selective activity-based profiling of ERK signaling. CHEMICAL SCIENCE, 9(9), 2419-2431. doi:10.1039/c8sc00043c

Manterola, A., Bernal-Chico, A., Cipriani, R., Ruiz, A., Perez-Samartin, A., Moreno-Rodriguez, M., . . . Mato, S. (2018). Re-examining the potential of targeting ABHD6 in multiple sclerosis: Efficacy of systemic and peripherally restricted inhibitors in experimental autoimmune encephalomyelitis. NEUROPHARMACOLOGY, 141, 181-191. doi:10.1016/j.neuropharm.2018.08.038

Campbell, S. T., Franks, C. E., Borne, A. L., Shin, M., Zhang, L., & Hsu, K. -L. (2018). Chemoproteomic Discovery of a Ritanserin-Targeted Kinase Network Mediating Apoptotic Cell Death of Lung Tumor Cells. MOLECULAR PHARMACOLOGY, 94(5), 1246-1255. doi:10.1124/mol.118.113001

Curry, Z. A., Wilkerson, J. L., Bagdas, D., Kyte, S. L., Patel, N., Donvito, G., . . . Lichtman, A. H. (2018). Monoacylglycerol Lipase Inhibitors Reverse Paclitaxel-Induced Nociceptive Behavior and Proinflammatory Markers in a Mouse Model of Chemotherapy-Induced Neuropathy. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 366(1), 169-183. doi:10.1124/jpet.117.245704

Wilkerson, J. L., Curry, Z. A., Kinlow, P. D., Mason, B. L., Hsu, K. -L., van der Stelt, M., . . . Lichtman, A. H. (2018). Evaluation of different drug classes on transient sciatic nerve injury-depressed marble burying in mice. PAIN, 159(6), 1155-1165. doi:10.1097/j.pain.0000000000001199

2017

McCloud, R. L., Franks, C. E., Campbell, S. T., Purow, B. W., Harris, T. E., & Hsu, K. -L. (2018). Deconstructing Lipid Kinase Inhibitors by Chemical Proteomics. BIOCHEMISTRY, 57(2), 231-236. doi:10.1021/acs.biochem.7b00962

Shin, M., Snyder, H. W., Donyito, G., Schurman, L. D., Fox, T. E., Lichtman, A. H., . . . Hsu, K. -L. (2018). Liposomal Delivery of Diacylglycerol Lipase-Beta Inhibitors to Macrophages Dramatically Enhances Selectivity and Efficacy in Vivo. MOLECULAR PHARMACEUTICS, 15(3), 721-728. doi:10.1021/acs.molpharmaceut.7b00657

Yun, B., Lee, H., Powell, R., Reisdorph, N., Ewing, H., Gelb, M. H., . . . Leslie, C. C. (2017). Regulation of calcium release from the endoplasmic reticulum by the serine hydrolase ABHD2. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 490(4), 1226-1231. doi:10.1016/j.bbrc.2017.06.195

Franks, C. E., Campbell, S. T., Purow, B. W., Harris, T. E., & Hsu, K. -L. (2017). The Ligand Binding Landscape of Diacylglycerol Kinases. CELL CHEMICAL BIOLOGY, 24(7), 870-+. doi:10.1016/j.chembiol.2017.06.007

2016

Buczynski, M. W., Herman, M. A., Hsu, K. -L., Natividad, L. A., Irimia, C., Polis, I. Y., . . . Parsons, L. H. (2016). Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposure. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 113(4), 1086-1091. doi:10.1073/pnas.1522672113

Wilkerson, J. L., Ghosh, S., Bagdas, D., Mason, B. L., Crowe, M. S., Hsu, K. L., . . . Lichtman, A. H. (2016). Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. BRITISH JOURNAL OF PHARMACOLOGY, 173(10), 1678-1692. doi:10.1111/bph.13469

2015

Baggelaar, M. P., Chameau, P. J. P., Kantae, V., Hummel, J., Hsu, K. -L., Janssen, F., . . . van der Stelt, M. (2015). Highly Selective, Reversible Inhibitor Identified by Comparative Chemoproteomics Modulates Diacylglycerol Lipase Activity in Neurons. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 137(27), 8851-8857. doi:10.1021/jacs.5b04883

Kohnz, R. A., Mulvihill, M. M., Chang, J. W., Hsu, K. -L., Sorrentino, A., Cravatt, B. F., . . . Nomura, D. K. (2015). Activity-Based Protein Profiling of Oncogene-Driven Changes in Metabolism Reveals Broad Dysregulation of PAFAH1B2 and 1B3 in Cancer. ACS CHEMICAL BIOLOGY, 10(7), 1624-1630. doi:10.1021/acschembio.5b00053

Chang, J. W., Zuhl, A. M., Speers, A. E., Niessen, S., Brown, S. J., Mulvihill, M. M., . . . Cravatt, B. F. (2015). Selective Inhibitor of Platelet-Activating Factor Acetylhydrolases 1b2 and 1b3 That Impairs Cancer Cell Survival. ACS CHEMICAL BIOLOGY, 10(4), 925-932. doi:10.1021/cb500893q

2014

Manna, J. D., Wepy, J. A., Hsu, K. -L., Chang, J. W., Cravatt, B. F., & Marnett, L. J. (2014). Identification of the Major Prostaglandin Glycerol Ester Hydrolase in Human Cancer Cells. JOURNAL OF BIOLOGICAL CHEMISTRY, 289(49), 33741-33753. doi:10.1074/jbc.M114.582353

Grim, T. W., Ghosh, S., Hsu, K. -L., Cravatt, B. F., Kinsey, S. G., & Lichtman, A. H. (2014). Combined inhibition of FAAH and COX produces enhanced anti-allodynic effects in mouse neuropathic and inflammatory pain models. PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 124, 405-411. doi:10.1016/j.pbb.2014.07.008

Yun, B., Lee, H., Ghosh, M., Cravatt, B. F., Hsu, K. -L., Bonventre, J. V., . . . Leslie, C. C. (2014). Serine Hydrolase Inhibitors Block Necrotic Cell Death by Preventing Calcium Overload of the Mitochondria and Permeability Transition Pore Formation. JOURNAL OF BIOLOGICAL CHEMISTRY, 289(3), 1491-1504. doi:10.1074/jbc.M113.497651

Agrawal, P., Kurcon, T., Pilobello, K. T., Rakus, J. F., Koppolu, S., Liu, Z., . . . Mahal, L. K. (2014). Mapping posttranscriptional regulation of the human glycome uncovers microRNA defining the glycocode. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(11), 4338-4343. doi:10.1073/pnas.1321524111

Inloes, J. M., Hsu, K. -L., Dix, M. M., Viader, A., Masuda, K., Takei, T., . . . Cravatt, B. F. (2014). The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(41), 14924-14929. doi:10.1073/pnas.1413706111

Naydenov, A. V., Horne, E. A., Cheah, C. S., Swinney, K., Hsu, K. -L., Cao, J. K., . . . Stella, N. (2014). ABHD6 Blockade Exerts Antiepileptic Activity in PTZ-Induced Seizures and in Spontaneous Seizures in R6/2 Mice. NEURON, 83(2), 361-371. doi:10.1016/j.neuron.2014.06.030

2013

Dominguez, E., Galmozzi, A., Chang, J. W., Hsu, K. -L., Pawlak, J., Li, W., . . . Saez, E. (2014). integrated phenotypic and activity-based profiling links Ces3 to obesity and diabetes. NATURE CHEMICAL BIOLOGY, 10(2), 113-121. doi:10.1038/nchembio.1429

Hsu, K. -L., Tsuboi, K., Whitby, L. R., Speers, A. E., Pugh, H., Inloes, J., & Cravatt, B. F. (2013). Development and Optimization of Piperidyl-1,2,3-Triazole Ureas as Selective Chemical Probes of Endocannabinoid Biosynthesis. JOURNAL OF MEDICINAL CHEMISTRY, 56(21), 8257-8269. doi:10.1021/jm400898x

Hsu, K. -L., Tsuboi, K., Chang, J. W., Whitby, L. R., Speers, A. E., Pugh, H., & Cravatt, B. F. (2013). Discovery and Optimization of Piperidyl-1,2,3-Triazole Ureas as Potent, Selective, and in Vivo-Active Inhibitors of α/β-Hydrolase Domain Containing 6 (ABHD6). JOURNAL OF MEDICINAL CHEMISTRY, 56(21), 8270-8279. doi:10.1021/jm400899c

2012

Nagano, J. M. G., Hsu, K. -L., Whitby, L. R., Niphakis, M. J., Speers, A. E., Brown, S. J., . . . Cravatt, B. F. (2013). Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A2. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 23(3), 839-843. doi:10.1016/j.bmcl.2012.11.061

Hsu, K. -L., Tsuboi, K., Adibekian, A., Pugh, H., Masuda, K., & Cravatt, B. F. (2012). DAGLβ inhibition perturbs a lipid network involved in macrophage inflammatory responses. NATURE CHEMICAL BIOLOGY, 8(12), 999-1007. doi:10.1038/NCHEMBIO.1105

Adibekian, A., Martin, B. R., Chang, J. W., Hsu, K. -L., Tsuboi, K., Bachovchin, D. A., . . . Cravatt, B. F. (2012). Confirming Target Engagement for Reversible Inhibitors in Vivo by Kinetically Tuned Activity-Based Probes. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 134(25), 10345-10348. doi:10.1021/ja303400u

Zuhl, A. M., Mohr, J. T., Bachovchin, D. A., Niessen, S., Hsu, K. -L., Berlin, J. M., . . . Cravatt, B. F. (2012). Competitive Activity-Based Protein Profiling Identifies Aza-β-Lactams as a Versatile Chemotype for Serine Hydrolase Inhibition. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 134(11), 5068-5071. doi:10.1021/ja300799t

2011

Adibekian, A., Martin, B. R., Wang, C., Hsu, K. -L., Bachovchin, D. A., Niessen, S., . . . Cravatt, B. F. (2011). Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors. NATURE CHEMICAL BIOLOGY, 7(7), 469-478. doi:10.1038/NCHEMBIO.579

Hsu, K. -L., Pilobello, K., Krishnamoorthy, L., & Mahal, L. K. (2011). Ratiometric Lectin Microarray Analysis of the Mammalian Cell Surface Glycome. BIOLOGICAL MICROARRAYS: METHODS AND PROTOCOLS, 671, 117-131. doi:10.1007/978-1-59745-551-0_6

Propheter, D. C., Hsu, K. -L., & Mahal, L. K. (2011). Recombinant Lectin Microarrays for Glycomic Analysis. PROTEIN MICROARRAY FOR DISEASE ANALYSIS: METHODS AND PROTOCOLS, 723, 67-77. doi:10.1007/978-1-61779-043-0_6

2010

Propheter, D. C., Hsu, K. -L., & Mahal, L. K. (2010). Fabrication of an Oriented Lectin Microarray. CHEMBIOCHEM, 11(9), 1203-1207. doi:10.1002/cbic.201000106