Identification and in vitro experimental investigation of missense SNPs implicate

错义 SNP 的鉴定和体外实验研究

基本信息

  • 批准号:
    8366038
  • 负责人:
  • 金额:
    $ 28.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Recent genome wide association studies have led to the reliable identification of multiple genomic loci where the presence of common SNPs is associated with altered risk of a number of common human diseases. These results offer the prospect of new insights into the nature of complex trait disease in general and specific understanding of the mechanisms underlying major common human diseases. Deriving insight into these underlying mechanisms is not trivial, and requires the development and application of a range of computational and experimental techniques. Molecular processes constitute a key part of the multiple level mechanisms by which SNPs influence disease risk, and a full understanding of their contributions is essential to effective investigation of higher level pathwa and subsystems impact, as well as evaluation of potential drug targets. This project focuses on the role of missense SNPs (those that result in an amino acid substitution in a protein) in disease mechanism. It is now clear that this class of SNP plays a substantial role in common disease mechanisms. We focus on loci associated with increased risk of Crohn's disease, where association studies have been particularly successful in identifying disease relevant loci. Previously developed computational methods are used to identify which of these SNPs are expected to have a large impact on the in vivo molecular function of the corresponding protein, and thus are most likely to be involved in disease mechanism. Currently, there are 39 proteins in 25 loci that have candidate high impact missense SNPs. Results of this analysis are combined with other available information to prioritize proteins for experimental study. In order to determine the precise effect on protein function, we will clone, express and purify a number of the high priority proteins and their SNP variants, and investigate in vitro properties, particularl structural stability and interaction with appropriate binding partners. We have demonstrated the power of this strategy for the case of macrophage stimulating factor (MSP), found to carry a candidate mechanism SNP for Crohn's disease, by establishing that binding to a cell surface receptor is impaired, implying down regulation of macrophage activity. Results of the experimental work together with computational modeling and annotation for all the Crohn's disease loci will made available through an online database and annotation facility, so that the results can be maximally exploited. PUBLIC HEALTH RELEVANCE: New data are for the first time reliably establishing many associations between genetic variation among individuals and susceptibility to a number of common human diseases. These data open the way for investigation of the mechanisms underlying disease and hence the development of new therapies. This project will use computational and experimental methods to determine protein level mechanisms underlying disease loci for Crohn's, an inflammatory bowel disease.
描述(由申请人提供):最近的全基因组关联研究已经可靠地鉴定了多个基因组位点,其中常见 SNP 的存在与许多常见人类疾病的风险改变相关。这些结果为人们对复杂性状疾病的一般性质和对人类主要常见疾病的机制的具体理解提供了新的见解。深入了解这些潜在机制并非易事,需要开发和应用一系列计算和实验技术。分子过程构成了 SNP 影响疾病风险的多层次机制的关键部分,充分了解其贡献对于有效研究更高层次的路径和子系统影响以及评估潜在的药物靶标至关重要。该项目重点研究错义 SNP(导致蛋白质中氨基酸取代的 SNP)在疾病机制中的作用。现在已经清楚,此类 SNP 在常见疾病机制中发挥着重要作用。我们重点关注与克罗恩病风险增加相关的位点,其中关联研究在识别疾病相关位点方面特别成功。先前开发的计算方法用于识别这些 SNP 中的哪些预计会对相应蛋白质的体内分子功能产生较大影响,因此最有可能参与疾病机制。目前,25 个位点中有 39 个蛋白质具有候选高影响错义 SNP。该分析的结果与其他可用信息相结合,以确定实验研究中蛋白质的优先顺序。为了确定对蛋白质功能的精确影响,我们将克隆、表达和纯化一些高优先级蛋白质及其 SNP 变体,并研究体外特性,特别是结构稳定性以及与适当结合伴侣的相互作用。我们通过确定巨噬细胞刺激因子 (MSP) 与细胞表面受体的结合受损(意味着巨噬细胞活性下调)证明了该策略的威力,巨噬细胞刺激因子 (MSP) 被发现携带克罗恩病的候选机制 SNP。实验工作的结果以及所有克罗恩病基因座的计算模型和注释将通过在线数据库和注释设施提供,以便最大限度地利用结果。 公共卫生相关性:新数据首次可靠地确立了个体遗传变异与多种常见人类疾病易感性之间的许多关联。这些数据为研究疾病的机制以及开发新疗法开辟了道路。该项目将使用计算和实验方法来确定克罗恩病(一种炎症性肠病)疾病位点的蛋白质水平机制。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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OSNAT HERZBERG其他文献

OSNAT HERZBERG的其他文献

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{{ truncateString('OSNAT HERZBERG', 18)}}的其他基金

Fumagillin Derivatives as Novel Antigiardiasis and Antiamebiasis Drugs
夫马洁林衍生物作为新型抗贾第鞭毛虫病和抗阿米巴病药物
  • 批准号:
    9089862
  • 财政年份:
    2015
  • 资助金额:
    $ 28.88万
  • 项目类别:
Fumagillin Derivatives as Novel Antigiardiasis and Antiamebiasis Drugs
夫马洁林衍生物作为新型抗贾第鞭毛虫病和抗阿米巴病药物
  • 批准号:
    8960227
  • 财政年份:
    2015
  • 资助金额:
    $ 28.88万
  • 项目类别:
Identification and in vitro experimental investigation of missense SNPs implicate
错义 SNP 的鉴定和体外实验研究
  • 批准号:
    8534208
  • 财政年份:
    2012
  • 资助金额:
    $ 28.88万
  • 项目类别:
Identification and in vitro experimental investigation of missense SNPs implicate
错义 SNP 的鉴定和体外实验研究
  • 批准号:
    8735958
  • 财政年份:
    2012
  • 资助金额:
    $ 28.88万
  • 项目类别:
Compound library screening using Giardia labmblia high throughput viability assay
使用贾第鞭毛虫高通量活力测定筛选化合物库
  • 批准号:
    8204416
  • 财政年份:
    2010
  • 资助金额:
    $ 28.88万
  • 项目类别:
Compound library screening using Giardia labmblia high throughput viability assay
使用贾第鞭毛虫高通量活力测定筛选化合物库
  • 批准号:
    8069710
  • 财政年份:
    2010
  • 资助金额:
    $ 28.88万
  • 项目类别:
Structure-Function studies of human hyaluronidases
人类透明质酸酶的结构-功能研究
  • 批准号:
    7778818
  • 财政年份:
    2009
  • 资助金额:
    $ 28.88万
  • 项目类别:
Mechanisms of action of SNPs associated with common disease
SNP与常见疾病相关的作用机制
  • 批准号:
    7713409
  • 财政年份:
    2009
  • 资助金额:
    $ 28.88万
  • 项目类别:
Structure-Function studies of human hyaluronidases
人类透明质酸酶的结构-功能研究
  • 批准号:
    8081238
  • 财政年份:
    2009
  • 资助金额:
    $ 28.88万
  • 项目类别:
Structure-Function studies of human hyaluronidases
人类透明质酸酶的结构-功能研究
  • 批准号:
    8074616
  • 财政年份:
    2009
  • 资助金额:
    $ 28.88万
  • 项目类别:

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