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Role of Human-Specific Cathepsin V Protease in the Production of Opioid and Related Peptide Neurotransmitters

人类特异性组织蛋白酶 V 蛋白酶在阿片类药物和相关肽神经递质生产中的作用

基本信息

批准号：
9215425
负责人：
Vivian Y. H Hook
金额：
$ 15.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9215425
关键词：
Absence of pain sensation Address Age-Years Aging Amino Acid Sequence Anabolism Animal Model Behavior Biochemical Brain Brain region Cathepsin L Cathepsins Cell model Chemicals Cognition Data Disease Dynorphins Enkephalins Environmental Impact Environmental Risk Factor Funding Opportunities Gene Expression Gene Silencing Generations Genes Goals Health Homologous Gene Human Immunofluorescence Microscopy In Vitro Kinetics Knowledge Lead Mass Spectrum Analysis Mental Health Modeling Mus Nervous System Physiology Neurologic Neurons Neuropeptides Neurosciences Neurotransmitters Opioid Pathway interactions Peptide Hydrolases Peptides Pharmaceutical Preparations Process Production Property Proprotein Convertase 1 Proprotein Convertase 2 Proprotein Convertases Protein Precursors Regulation Role Secretory Vesicles Site Stress beta-Endorphin brain tissue drug of abuse in vivo induced pluripotent stem cell innovation interest mind control neurotransmission protease V prototype response small molecule

项目摘要

DESCRIPTION (provided by applicant): This project addresses the fundamental question of "What `human' protease mechanisms are responsible for producing active peptide neurotransmitters, neuropeptides, that are a fundamental requirement for all brain and nervous system functions?" The unique hypothesis to address this question is that human-specific cathepsin V, combined with proteases identified in non-human animal models for neuropeptide production, participates in producing active neuropeptides. Fundamental knowledge of the human protease mechanisms for producing neuropeptides are relevant to neuropeptide regulation in neurological and mental health throughout aging, and which are impacted by environmental conditions including drugs of abuse. Studies in mice have demonstrated the important role of mouse cathepsin L in secretory vesicles for producing opioid and other neuropeptides. Interestingly, human-specific cathepsin V is the closest human homologue to mouse cathepsin L, suggesting a role for cathepsin V in neuropeptide production. The human-specific cathepsin V gene is not present in mouse or other species. We investigated human cathepsin V and found that it participates as a significant protease for enkephalin neuropeptide production. These findings lead to the goal of this `human focused' project to define the human protease mechanisms for neuropeptide production by cathepsin V, combined with cathepsin L and the PC1/3 & PC2 convertases that function in non-human species for neuropeptide production. Human induced pluripotent stem cell (hiPSC) neurons produce numerous neuropeptides and will be used as an innovative model for human protease mechanisms in neuropeptide biosynthesis. Parallel studies of neuropeptides and processing proteases in human brain regions rich in neuropeptides will support findings gained from the hiPSC model. Innovative neuropeptidomics mass spectrometry will identify neuropeptide profiles in an unbiased and high throughput manner. The first aim will define the cellular role in hiPSC neurons of cathepsin V in the production of opioid neuropeptides with comparison to cathepsin L, PC1/3, and PC2 proteases by gene silencing and expression, combined with mass spectrometry peptide identifications. The second aim will conduct in vitro biochemical studies of cathepsin V processing of opioid pro-neuropeptides compared to cathepsin L, PC1/3, and PC2, to define cleavage sites, peptide products, and kinetic efficiencies, with parallel analyses in human brain regions. The third aim will investigate diverse neuropeptides by neuropeptidomics of hiPSC neurons and human brain tissues to evaluate the role of these human proteases in producing diverse neuropeptides. Results will define the basic human protease mechanisms for peptide neurotransmitter production that is fundamental for brain and nervous system functions in health and disease.