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Novel Probes for Sirtuins: A Chemical Biology Approach

Sirtuins 的新型探针：化学生物学方法

基本信息

批准号：
9303505
负责人：
Martha A. Hass
金额：
$ 48万
依托单位：
ALBANY COLLEGE OF PHARMACY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303505
关键词：
Academia Active Sites Aging-Related Process Alkynes Apoptosis Applications Grants Biogenesis Biological Biological Models Biological Process Biology Biotin Caloric Restriction Cell Cycle Regulation Cell physiology Cells Chemicals Chemistry Complex Conflict (Psychology)Cues DNA Repair Data Deacetylase Detection Disease Disease Progression Drug Industry Ensure Enzymes Epigenetic Process Event Family Fluorescent Dyes Gene Silencing Genetic Transcription Goals Health Benefit Histones Human Image Immunofluorescence Immunologic In Vitro Investigation Label Lead Libraries Link Lysine Malignant Neoplasms Mammalian Cell Mass Spectrum Analysis Measures Mediating Metabolic Metabolic Diseases Metabolism Microscopy Mitochondria Molecular Biology Multienzyme Complexes Niacinamide Nicotinamide adenine dinucleotide O-Acetyl-ADP-Ribose Outcome Pathogenesis Pathologic Peptides Permeability Photoaffinity Labels Physiological Physiological Processes Play Post-Translational Protein Processing Process Property Protein Isoforms Proteins Proteome Proteomics Recombinants Regulation Reporter Reporting Research Role SIRT1 gene Sampling Signal Transduction Sirtuins Site-Directed Mutagenesis Stimulus Techniques Technology Testing Ultraviolet Rays Validation Western Blotting age related base cellular imaging design enzyme activity experimental study functional group imaging study improved inhibitor/antagonist innovation interest novel novel therapeutics protein expression protein protein interaction response scaffold small molecule targeted treatment therapeutic target tool tool development

项目摘要

PROJECT SUMMARY Sirtuins, also called Class III HDACs, consume stoichiometric amounts of nicotinamide adenine dinucleotide (NAD+) to remove acetyl group from lysine residues and to produce nicotinamide and O-acetyl-ADP-ribose. This intriguing class of enzymes has been implicated in regulating various cellular events and has also been suggested to mediate the beneficial effects of calorie restriction (CR). Sirtuins have been intensely pursued by academia and pharmaceutical industry as therapeutic targets. However, controversies on sirtuin biology also peaked during the last few years because of conflicting results from different research groups. This is partly because these enzymes have been discovered recently, and the intricate interaction loops between sirtuins and other proteins make the characterization of them extremely difficult. One of the daunting tasks is to correlate sirtuin activity to disease pathogenesis. Current molecular biology and proteomics techniques report protein abundance rather than active sirtuin content. Innovative chemical tools that can directly probe the functional state of sirtuins are desperately needed. This grant application proposes to take a highly integrative approach to interrogate the functional state of sirtuins in complex biological samples. Our preliminary results demonstrate the feasibility of this strategy. We have obtained a set of powerful chemical probes that are capable of assessing the active content of sirtuins in model systems. In this proposal we plan to synthesize focused libraries of activity-based chemical probes. The scaffolds are designed for enhanced selectivity and labeling efficiency. The probes that score favorably in labeling of recombinant sirtuins will be subjected to the profiling of whole cell lysate. In complex native proteome, the probe should selectively “highlight” the active sirtuin components. Combined with mass spectrometry based proteomics analysis, this strategy should unveil the functional profile of sirtuins under different physiological and pathological conditions. This will provide information on how abnormal enzyme activity will contribute to disease progression. Furthermore, cell permeable probes will also be employed in cellular imaging study. It will enable the simultaneous detection of functional state and localization and empower the direct analysis of sirtuin function in response to cellular and environmental cues.

项目总结