Dr. Hook: Neurological Disease Peptide and Protease Mechanisms for Drug Discovery

Research Summary: Proteases for Production of Neuropeptide Transmitters in Neurological Disease, and Toxic Peptides in

Neurodegenerative Diseases for Drug Target Strategies

The focus of research in the Hook Laboratory is to understand how proteases and protease inhibitors participate in (1) protease pathways required for converting precursors into active opioid neuropeptides and others, that function as neurotransmitters and peptide hormones in health and disease, with pharmacological strategies, (2) proteases that generate neurotoxic peptides in Alzheimer's disease and neurodegenerative diseases, (3) application of new protease mechanisms to drug discovery, including pharmacogenetic features, (4) peptidomics proteomics by mass spectrometry for translation as biomarkers into clinical therapeutics. This research can lead to development of novel drug therapeutics for disease and health.

Academic Achievements

Education: B.S. in Biomedical Sciences, UC Berkeley; Ph.D. in Pharmacology (year) UC San Francisco.

Awards and Honors: Pharmacology Research Fellow (PRAT), Burroughs Wellcome Scientist Award (NIH Career Award, J & J Focused Giving Award
NIH grant review committee memberships.

Leadership Experience: Chair of the Faculty EPAOC Committee, Chair ISPPSCAP Academic Review Committee, Co-Chair Research Committee, Co-Chair Faculty Recruitment Committee, Director of NIH Training Program ‘Neuroscience Related to Drugs of Abuse,’ Biotechnology.

Teaching

• Pharmaceutical Biochemistry for pharmacy students; Cell Biology and Biochemistry for medical/pharmacy students; Molecular Neuroendocrinology, Molecular Neurobiology, Proteomics, Drug Mechanisms, and Research Proposal Design for graduate students.

Key Contributions to Pharmaceutical Sciences

• Proteases for Neurotransmitter and Hormone Cell Cell Communication in Disease. Distinct cathepsin L and convertase pathways for neuropeptide production in endocrine cells have been defined. Pharmacological features of these protease mechanisms are being investigated for novel drug targets in pain, neurodegenerative diseases, hypertension, and cancer.
• Alzheimer’s Disease and Neurodegenerative Disease Search for Drug Targets. Alzheimer’s disease and neurodegenerative diseases overproduce neurotoxic peptides generated from protein precursors. Proteases that produce the toxic peptides are key drug targets that can lead to novel therapeutic agents. The Hook lab discovered a novel protease drug target for AD.
• Peptidomics and Proteases in Human Diseases: Drug Targets and Biomarkers. Mass spectrometry-based identification of novel peptides in human diseases are being investigated for elucidation of novel drug targets, and for clinical applications as biomarkers to monitor disease progression and drug response.

Selected Recent Publications: (from over 140)

Hook et al. (2008). Proteases for processing proneuropeptides into peptide neurotransmitters and hormones. Annu. Rev. Pharmacol. Tox. 48:393-423.

Funkelstein et al. (2008). Major role of cathepsin L for producing the peptide hormones ACTH, beta- endorphin, and alpha-MSH, illustrated by protease gene knockout and expression. J. Biol. Chem. 283: 35652-35659.

Hook et al. (2008). Inhibitors of cathepsin B improve memory and reduce Abeta in transgenic Alzheimer's disease mice. J. Biol. Chem. 283:7745-7753.

Gupta et al. (2010). Mass spectrometry-based neuropeptidomics of secretory vesicles from human adrenal medullary pheochromocytoma reveals novel peptide products of prohormone processing. J Proteome Res. 9:5065-75

Potential Collaboration Programs with Pharmaceutical Industry and Biotech

• Protease strategies for drug screening.
• Proteomics and peptidomics for disease Biomarkers.
• Neurological diseases including chronic pain, stress, neurodegenerative diseases including Alzheimer’s and Huntington’s diseases.
• Hypertension and cardiovascular disease.
• Cancer, endocrine features.