权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Comparative and Functional Genomics of Protein Kinases

蛋白激酶的比较和功能基因组学

基本信息

批准号：
7776913
负责人：
Gerard Manning
金额：
$ 40.65万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-15 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7776913
关键词：
Atlases Attention Behavior Biological Models Biological Process Cataloging Catalogs Cell physiology Cells Code Complex Conserved Sequence DNA Resequencing Data Decision Making Detection Development Disease Evolution Family Floods Gene Family Genes Genetic Genetic Polymorphism Genome Growth Human Knowledge Link Malignant Neoplasms Manuals Maps Measures Methods Modeling Mus Mutation Orthologous Gene Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phosphorylation Phosphorylation Site Phosphotransferases Post-Translational Modification Site Protein Kinase Protein Region Proteins Reading Research Personnel Resolution Silent Mutation Somatic Mutation Source Testing Translating Variant Vertebrates base cancer genome comparative comparative genomics experimental analysis functional genomics genome sequencing genome-wide human disease improved member novel novel strategies pressure programs research study response tool tumor vertebrate genome

项目摘要

DESCRIPTION (provided by applicant): Project Summary: 518 human protein kinases modulate the activity of -30% of all proteins, and collectively control almost all complex pathways and decisions of a cell. Despite tremendous experimental analysis on some kinases, we know little of the detailed function of most members of this uniquely important family. We propose to use genome sequences to tap hundreds of millions of years of evolutionary experimentation, in order to clarify the link between kinase sequence and biological function. We will use our extensive knowledge from the discovery of the human and mouse kinomes to predict all kinase orthologs in up to 40 vertebrate genomes. We will then map the evolutionary constraints on every residue of every kinase, and predict domains, motifs, phosphorylation sites, and other functional regions of proteins, extending the kinome catalog to unprecedented resolution and generating a wealth of hypotheses for experimental testing. Finally, we will apply this knowledge to predict the functional impact of both SNPs and somatic mutations in cancer, providing a valuable preview of the proposed cancer genome atlas. By using kinases as a model family to explore the predictive power of comparative genomics, we will develop well-validated tools and parameters which can then be applied to any human gene or gene family. Relevance: Protein kinases key controllers of cell function, are one of the most important gene families in disease and development of new drug therapies. By exploring how human kinases vary from those of other vertebrates, we can predict whether any human sequence change can predispose to disease or alter drug response, and can distinguish cancer-driving mutations in tumors from background mutations.

描述(由申请人提供)：项目摘要：518个人类蛋白激酶调节-30%的所有蛋白质的活性，并共同控制几乎所有复杂的途径和细胞的决定。尽管对一些激酶进行了大量的实验分析，但我们对这个独特的重要家族中大多数成员的详细功能知之甚少。我们建议利用基因组序列来挖掘数亿年的进化实验，以澄清激酶序列与生物功能之间的联系。我们将使用我们从人类和小鼠基因组发现中获得的广泛知识来预测多达40个脊椎动物基因组中的所有激酶同源基因。然后，我们将绘制每个激酶残基的进化限制图，并预测蛋白质的结构域、基序、磷酸化位点和其他功能区域，将基因组目录扩展到前所未有的分辨率，并产生大量用于实验测试的假设。最后，我们将应用这些知识来预测SNPs和体细胞突变对癌症的功能影响，提供一个有价值的预览拟议的癌症基因组图谱。通过使用激酶作为模型家族来探索比较基因组学的预测能力，我们将开发出经过充分验证的工具和参数，然后可以应用于任何人类基因或基因家族。相关：蛋白激酶是细胞功能的关键控制者，是疾病和新药治疗开发中最重要的基因家族之一。通过探索人类激酶与其他脊椎动物的不同之处，我们可以预测人类序列的任何变化是否会导致疾病或改变药物反应，并可以区分肿瘤中的致癌突变和背景突变。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

How the vertebrates were made: selective pruning of a double-duplicated genome.

脊椎动物是如何形成的：双重复基因组的选择性修剪。

DOI：
10.1186/1741-7007-8-144
发表时间：
2010
期刊：
BMC biology
影响因子：
5.4
作者：
Manning,Gerard;Scheeff,Eric
通讯作者：
Scheeff,Eric

Structure of the pseudokinase VRK3 reveals a degraded catalytic site, a highly conserved kinase fold, and a putative regulatory binding site.

DOI：
10.1016/j.str.2008.10.018
发表时间：
2009-01-14
期刊：
Structure (London, England : 1993)
影响因子：
0
作者：
Scheeff ED;Eswaran J;Bunkoczi G;Knapp S;Manning G
通讯作者：
Manning G

The Raine syndrome protein FAM20C is a Golgi kinase that phosphorylates bio-mineralization proteins.

DOI：
10.1371/journal.pone.0042988
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Ishikawa HO;Xu A;Ogura E;Manning G;Irvine KD
通讯作者：
Irvine KD

Genomics, evolution, and crystal structure of a new family of bacterial spore kinases.

DOI：
10.1002/prot.22663
发表时间：
2010-05-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
影响因子：
2.9
作者：
Scheeff, Eric D.;Axelrod, Herbert L.;Miller, Mitchell D.;Chiu, Hsiu-Ju;Deacon, Ashley M.;Wilson, Ian A.;Manning, Gerard
通讯作者：
Manning, Gerard

The Amphimedon queenslandica genome and the evolution of animal complexity.