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Sir2 regulation and chemical modulation

Sir2调节和化学调节

基本信息

批准号：
8006734
负责人：
ANTHONY A. SAUVE
金额：
$ 4.69万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-31 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8006734
关键词：
Abbreviations Achievement Adenine Adenosine Diphosphate Ribose Animals Apoptosis Binding Biochemical Biochemistry Biological Caloric Restriction Cardiovascular Diseases Catalysis Cell Survival Cells Cellular Stress Chemicals Chemistry Chromatin Deacetylase Deacetylation Degenerative Disorder Development Diabetes Mellitus Dinucleoside Phosphates Enzymes Event Gene Expression Gene Silencing Genetic Goals Health Health Benefit Histones Human Insulin Resistance Intervention Knowledge Longevity Mammalian Cell Mammals Mass Spectrum Analysis Mediating Metabolic Methods Mus Nerve Degeneration Niacinamide Nicotinamide Mononucleotide Nicotinamide adenine dinucleotide O-Acetyl-ADP-Ribose Organism Patients Peroxisome Proliferator-Activated Receptors Proteins Reaction Regulation Research Research Personnel Resistance Ribose Sirtuins Stress TP53 gene Testing Therapeutic Tissues Yeasts base chemical reaction derepression design human sirtuin 1 improved in vitro activity in vivo insight insulin sensitivity interest isonicotinamide lipid biosynthesis nicotinate nicotinate mononucleotide novel strategies novel therapeutics programs response small molecule transcription factor

项目摘要

The objective of the proposed research is to deduce mechanistic and regulatory principles that control the activities of sirtuin enzymes in yeast and human cells. These principles will be used to design small molecules that can activate sirtuins in cells. Sirtuins regulate a host of biologically significant activities including stress resistance, gene silencing and longevity. Sirtuins are implicated in mediating biological effects associated with calorie restriction. Calorie restriction has been shown to have numerous positive health benefits in mammals including reduced adipogenesis, insulin sensitivity and increased lifespan. These biological effects have raised interest in the enzymatic mechanisms of sirtuins, the means by which they are regulated in cells and the ways in which they might be modulated pharmacologically for improved human health. Sirtuins are NAD dependent deacetylases that remove acetyl-groups of acetyllysine modified histones and transcription factors thereby regulating chromatin and gene expression. We and others have demonstrated that these actvitities are regulated by NAD and nicotinamide levels in cells, and that the sirtuins are able to integrate information from energy and metabolic states to control genetic events. As part of our goal to better understand the functions of these enzymes and how they can be modulated in cells we propose to investigate the following specific aims: In Aim1 we propose to characterize the biochemical functions of this unique class of enzymes, emphasizing their chemical novelty and the incorporation of NAD in deacetylation reactions. In Aim2 we propose to show how enzymatic activity provides a mechanism for nicotinamide regulation of sirtuin activity. In addition with a recently developed mass spectrometry method we hope to gain new insights into how nicotinamide regulates sirtuins in cells. In Aim 3 we explore the development of small molecule activators of sirtuins designed from knowledge of the sirtuin reaction mechanism and the mechanism of nicotinamide regulation. These activators embody a novel approach to upregulate sirtuin action in cells and provide a potential entrypoint for pharmacological intervention to increase cell stress resistance and cell survival. Achievement of these aims is expected to provide new insights into the biochemistry and regulation of these enzymes, and provide proof of concept for new therapeutics that can activate sirtuins to treat diabetes and degenerative disorders.

拟议研究的目的是推断控制的机制和调控原则

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Plasmodium falciparum Sir2 is an NAD+-dependent deacetylase and an acetyllysine-dependent and acetyllysine-independent NAD+ glycohydrolase.

DOI：
10.1021/bi800767t
发表时间：
2008-09-23
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
French, Jarrod B.;Cen, Yana;Sauve, Anthony A.
通讯作者：
Sauve, Anthony A.

Nicotinamide riboside kinase structures reveal new pathways to NAD+.

DOI：
10.1371/journal.pbio.0050263
发表时间：
2007-10-02
期刊：
PLOS BIOLOGY
影响因子：
9.8
作者：
Tempel, Wolfram;Rabeh, Wael M;Bogan, Katrina L;Belenky, Peter;Wojcik, Marzena;Seidle, Heather F;Nedyalkova, Lyudmila;Yang, Tianle;Sauve, Anthony A;Park, Hee-Won;Brenner, Charles
通讯作者：
Brenner, Charles

Crosstalk between poly(ADP-ribose) polymerase and sirtuin enzymes.

聚（ADP-核糖）聚合酶和沉默调节蛋白酶之间的串扰。