University of California, San Diego | Skaggs School of Pharmacy and Pharmaceutical Sciences
PROTEASE RESEARCH
Proteases for Neutrotransmission and Neurodegenerative Diseases: Applications to Therapeutic Agents
The focus of our research is to understand how proteases and protease inhibitors are responsible for (1) multi-step proteolytic pathways required for converting precursor proteins into active neuropeptides that function as neurotransmitters, and (2) the protease mechanisms responsible for neurological diseases, including chronic pain, Alzheimer's and Huntington's diseases, and (3) proteomic approaches for elucidation of protease components as potential drug targets and therapeutics. These disciplines strive to understand the proteolytic controls involved in generating 'beneficial' peptides that promote health, and 'detrimental' peptides in disease.
BIOCHEMISTRY, MOLECULAR AND CELL BIOLOGY, GENETICS, PROTEOMICS, NEUROPEPTIDOMICS, AND PHARMACEUTICAL SCIENCES
Protease Pathways
IPS, MEROPS Database. . .
Mass Spectrometry
Instruments, Analysis. . .
Bioinformatics
Databases, Software, Hardware. . .
PROTEOMICS
Proteomics is the study of proteins and their interactions with in complex biological systems. While this field is often associated with mass spectrometry, it is more useful to consier the proteomics in the context of an objective: to identify and understand the molecular basis of health and disease at the protein level in vivo. Achieving this objective will require (1) technological developments to resolve current instrument limitations and (2) multidisciplinary integration of biological and protein analysis technologies to answer important questions in both the biological sciences and molecular medicine. (more)
Recent Publications:
Hook, V., Yoon, M., Mosier, C., Ito, G., Podvin, S., Head, B.P., Rissman, R., O'Donoghue, A.J., Hook, G. (2020) Cathepsin B in neurodegeneration of Alzheimer's disease, traumatic brain injury, and related brain disorders. Biochim Biophys Acta Proteins Proteom. 1868, 140428.
Boutté, A.M., Hook, V., Thangavelu, B., Sarkis, G.A., Abbatiello, B.N., Hook, G., Jacobsen, J.S., Robertson, C.S., Gilsdorf, J., Yang, Z., Wang, K.K.W., Shear, D.A. (2020) Penetrating Traumatic Brain Injury Triggers Dysregulation of Cathepsin B Protein Levels Independent of Cysteine Protease Activity in Brain and Cerebral Spinal Fluid. J Neurotrauma 37(13),1574-1586.
Podvin, S., Jones, A., Liu, Q., Aulston, B., Ransom, L., Ames, J., Shen, G., Lietz, C.B., Jiang, Z., O'Donoghue, A.J., Winston, C., Ikezu, T., Rissman, R.A., Yuan, S., Hook, V. (2020) Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses. Mol Cell Proteomics 9, 1017-1034.
Yoon, M.C., Solania, A., Jiang, Z., Christy, M.P., Podvin, S., Mosier, C., Lietz, C.B., Ito, G., Gerwick, W.H., Wolan, D.W., Hook, G., O'Donoghue, A.J., Hook, V. (2021) Selective Neutral pH Inhibitor of Cathepsin B Designed Based on Cleavage Preferences at Cytosolic and Lysosomal pH Conditions. ACS Chem Biol. 16, 1628-1643.
Jiang, Z., Lietz, C.B., Podvin, S., Yoon, M.C., Toneff, T., Hook, V., O'Donoghue, A.J. (2021) Differential Neuropeptidomes of Dense Core Secretory Vesicles (DCSV) Produced at Intravesicular and Extracellular pH Conditions by Proteolytic Processing. ACS Chem Neurosci. 12, 2385-2398.
Campeau, A., Mills, R.H., Stevens, T., Rossitto, L.A., Meehan, M., Dorrestein, P., Daly, R., Nguyen, T.T., Gonzalez, D.J., Jeste, D.V., Hook V. (2021) Multi-omics of Human Plasma Reveals Molecular Features of Dysregulated Inflammation and Accelerated Aging in Schizophrenia. Molecular Psychiatry Nature 2021 Nov 5.
Podvin, S., Jones, A., Liu, Q., Aulston, B., Mosier, C., Ames, J., Winston, C., Lietz, C.B., Jiang, Z., O'Donoghue, A.J., Ikezu, T., Rissman, R.A., Yuan, S.H., Hook, V. (2021) Mutant Presenilin 1 Dysregulates Exosomal Proteome Cargo Produced by Human-Induced Pluripotent Stem Cell Neurons. ACS Omega 6(20), 13033-13056.
Boyarko, B., Hook, V. (2021) Human tau isoforms and proteolysis for production of toxic tau fragments in neurodegeneration. Frontiers in Neuroscience 15, 1-19.
Ashhurst, A.S., Tang, A.H., Fajtová, P., Yoon, M.C., Aggarwal, A., Bedding, M.J., Stoye, A., Beretta, L., Pwee, D., Drelich, A., Skinner, D., Li, L., Meek, T.D., McKerrow, J.H., Hook, V., Tseng, C.T., Larance, M., Turville, S., Gerwick, W.H., O'Donoghue, A.J., Payne, R.J. (2021) Potent Anti-SARS-CoV-2 Activity by the Natural Product Gallinamide A and Analogues via Inhibition of Cathepsin L. J Med Chem. 2021 Nov 3